Supplemental File
Evaluating Historical Candidate Genes For Schizophrenia
Farrell et al.
Table of Contents
Supplemental text from informed investigators ........................................................................................... 2
AKT1.............................................................................................................................................................................................................................. 2
CHRNA7 ....................................................................................................................................................................................................................... 2
COMT............................................................................................................................................................................................................................. 2
DAO and DAOA .......................................................................................................................................................................................................... 3
DISC1............................................................................................................................................................................................................................. 4
DRD2 ............................................................................................................................................................................................................................. 5
DRD3 ............................................................................................................................................................................................................................. 5
DTNPB1........................................................................................................................................................................................................................ 6
HTR2A........................................................................................................................................................................................................................... 6
NRG1 ............................................................................................................................................................................................................................. 7
RGS4 .............................................................................................................................................................................................................................. 8
Supplementary Figures .............................................................................................................................. 10
Figure S1. PGC SCZ mega-analysis vs. SZGene candidate gene meta-analysis .............................................................................10
Figure S2. Gene ratings from 24 schizophrenia geneticists .................................................................................................................11
Supplemental Tables ................................................................................................................................. 12
Table S1. Results for 59 markers in/near 25 schizophrenia candidate genes.............................................................................12
Table S2. Independent meta-analyses for historical genes published 2008-2014 ....................................................................14
Table S3. Candidate gene studies of DAO ....................................................................................................................................................15
Table S4. Candidate gene studies of DAOA .................................................................................................................................................19
References ................................................................................................................................................ 31
1
Supplemental text from informed investigators
AKT1
Personal communication from Drs Joseph Gogos and Maria Karayiorgou (Columbia University, New
York, NY, USA).
Authoritative investigator rating: 5
PGC schizophrenia PI mean rating: 2.5
The rating for AKT1 was 5 (very likely). We base this rating on the original integrative biological data,
subsequent work in various genetic animal models (including unpublished work from our labs) as well as
gene network analysis that implicates AKT1/GSK3beta signaling as a major node connected to many SCZ
candidate genes. 1,2
CHRNA7
Personal communication from Drs Robert Freedman and Sherry Leonard (University of Colorado,
Denver, CO, USA).
Authoritative investigator rating: 5
PGC schizophrenia PI mean rating: 2.9
Linkage to schizophrenia of the CHRNA7 gene, which codes for the α7-nicotinic receptor subunit, was first
observed using a physiological endophenotype, auditory P50 evoked potential inhibition, that had been
previously associated with schizophrenia and α-7 nicotinic receptor function (LOD 5.2) 3. Subsequent
study showed association of both schizophrenia and the P50 endophenotype with SNPs in the proximal
CHRNA7 promoter that decrease expression in vitro 4. This finding is consonant with several reports of
decreased expression of α7-nicotinic receptor subunits in post mortem schizophrenia samples 5. A SNP in
the more distal promoter has the most significant reported association, P=0.0009, African-American;
P=0.013, Caucasian 6. Perhaps the most persuasive evidence for the CHRNA7 gene’s role in schizophrenia
is the well-replicated finding of 15q13.3 CNV CHRNA7 deletions 7,8. CHRFAM7A, a partial duplication
containing CHRNA7 exons 5-10, which is only found in humans, also maps nearby on 15q 9, and
polymorphisms in CHRFAM7A are associated with schizophrenia (Sinkus 2009). CHRFAM7A product
subunits can associate with CHRNA7 subunits as part of the α7-nicotinic acetylcholine receptor, which is
a pentameric ring. Compared to a receptor composed entirely of CHRNA7 subunits, those incorporating
CHRFAM7A subunits have significantly decreased ion flux, which suggests that CHRFAM7A may limit
CHRNA7 function and thereby have an additional pathological role 10.
COMT
Personal communication from Dr Daniel R Weinberger (Lieber Institute, Johns Hopkins University
School of Medicine).
Authoritative investigator rating: 1 (main effect), 4 (epistatic effect)
PGC schizophrenia PI mean rating: 2.4
Catechol-o-methyl transferase (COMT) has been perhaps the most extensively studied candidate gene in
behavioral genetics since the initial report of an association with schizophrenia in 1996 11. Its popularity
is based on many factors, including that it is mapped to an early schizophrenia linkage region on
chromosome 22, it is contained within the 22q11 hemi-deletion critical region of the VCFS syndrome, and
it is involved in catecholamine metabolism, a virtually sacrosanct biochemistry of neurotransmitters
related to psychiatric disorders and their treatment. Since the initial report, over twenty independent
case control studies found significant association with common COMT variants and psychosis, with
another ten family based studies also showing significant association 12. Even an early genome-wide
association study found a nominally significant signal in COMT 13. COMT shows significant association
signals in the current SZGene meta-analysis 12 and has been linked with psychosis in cases with
velocardiofacial syndrome (VCFS) 14,15. COMT also has been shown in several studies to interact with
environmental risk factors associated with psychosis (e.g. cannabis) 16,17. Most of the early studies
2
focused on a common coding variant with established effect on enzyme activity, the Val158Met variation,
but recent reports have emphasized signals in other polymorphisms. In addition to these associations
with clinical diagnosis, beginning with the first study of association of COMT with cognition and cortical
physiology 18 and with evidence that COMT is primarily involved in cortical dopamine flux 19, over 50
reports have documented a role for COMT in cortical information processing, establishing a biologic basis
for understanding a potential mechanism of association of COMT with behavioral syndromes. Virtually all
of the clinical associations of COMT with aspects of cortical function related to cognition and emotion
have been confirmed in studies of genetically engineered mice with analogous COMT variation 20-22.
Given these multiple positive reports of clinical association with albeit relatively small samples and the
elaboration of a biological mechanism by which COMT could influence brain function linked to psychosis
and other psychiatric disorders, why has association been so decidedly negative at the single locus level
in the current incarnation of GWAS data? And is the prior evidence of a role of COMT in brain function
related to psychiatric disorders a “red herring”? A reasoned response to these questions is that the jury is
still out on both counts. The failure to find association in the current GWAS data may reflect interactions
with modifying factors and the biologic heterogeneity of functional variants within the COMT gene that
are not accounted for in the current GWAS single locus association analyses. Several functional
polymorphisms within the COMT gene have been implicated 23-25, each acting via different molecular
mechanisms, so their cumulative effects are complex. A recent study of molecular haplotypes in
individuals with VCFS showed that alleles at one variant have paradoxical effects on COMT expression
and enzyme activity in the context of alleles at other variants 14. There are considerable population
differences in allele frequencies at the various functional polymorphisms within COMT, adding
insuperable heterogeneity to single locus analyses. Sex effects on COMT associations also have been
identified in clinical studies and in mice 20,22. Another complication with association with COMT involves
the biology of cortical dopamine function. The relationship between cortical function and dopamine
activity is nonlinear 26 and thus, predictable relationships between single SNP allele load and clinical
biology may require multilocus and nonlinear (e.g. epistatic) models. A recent study in mice and in
humans demonstrated that the COMT Val158Met polymorphism shows opposite associations with
cortical function depending on haplotype at another gene (DTNBP1) that also influences cortical
dopamine signaling 27. Interestingly, one meta-analysis of COMT associations with psychosis suggested
that the strongest signal was a protective association with heterozygosity at the Val158Met variant,
implying that in a given context (i.e. varying genomes and environments), too much or too little COMT
mediated cortical dopamine could have similar associations 28. Such effects would literally obliterate
single locus association in heterogeneous samples such as current GWAS. It is reasonable to assume that
COMT is a genetic risk factor for psychiatric syndromes linked to cortical dopamine signaling, but
statistical confirmation of this association will require multifactorial and probably nonlinear genetic
models that address the critical role of context, both genomic and environmental.
DAO and DAOA
Personal communication from Drs Marcella Rietschel and Jens Treutlein (Central Institute of Mental
Health, University of Heidelberg, Mannheim, Germany).
Authoritative investigator rating: 3, 3
PGC schizophrenia PI mean rating: 2.2, 2.0
See Tables S2 and S3. The first report of an association between schizophrenia and variants in the genes
d-amino acid oxidase (DAO) and d-amino acid oxidase activator (DAOA, alias G72) was published in 2002.
In a sample of 213 schizophrenia patients and 241 controls from Canada, Chumakov et al. performed a
systematic investigation of SNPs in a 5-Mb segment of the 13q34 chromosomal region. Two of the six
nominally significant variants from this study were subsequently replicated in an independent
schizophrenia sample 29, and in a sample of patients with bipolar disorder 30. These two variants were
located in the DAOA gene, whose product interacts with DAO. DAO metabolizes D-serine, which is an
3
activator of NMDA glutamate receptors, and glutamatergic signaling has been implicated in the etiology
of psychotic symptoms and schizophrenia.
Since these genes were plausible candidates for psychiatric disorders, numerous studies attempted to
corroborate their involvement in schizophrenia, bipolar disorder, and related traits. To our knowledge, a
total of ~76 studies for DAOA and ~25 studies for DAO have tested markers in schizophrenia and related
phenotypes. However, the findings have been inconsistent. Furthermore, few findings remained
significant following correction for the number of SNPs tested.
Several meta-analyses of the role of DAOA in schizophrenia and bipolar disorder have been published.
The meta-analysis by Detera-Wadleigh & McMahon in 2006 31 included seven studies of schizophrenia
and three studies of bipolar disorder, and found association between schizophrenia and the markers
M12, M15, M22, M23, and M24. The meta-analysis by Shi et al. in 2008 32 included 23 studies, and
detected association between schizophrenia and the markers M18, M22, and M24. The meta-analysis by
Müller et al. in 2011 33 included 24 studies of schizophrenia and 11 studies of bipolar disorder, and
revealed association between schizophrenia and the marker M15. The most recent meta-analysis by Tan
et al. in 2014 34 included 46 studies (17,515 cases and 25,189 controls), and tested the markers M15,
M18, and M23. However, no significant finding was identified.
In summary, the available data provide no support for the hypothesis that variants in DAO or DAOA
confer risk for schizophrenia. This view is supported by the observation that the number of positive
findings in meta-analyses is inversely proportional to the number of studies examined. It could be argued,
however, that since the anticipated effect sizes are small, and that the effects of genetic variants will be
blurred by interaction with other factors, this inverse relationship is unsurprising when increasing
heterogeneity of the samples. Interestingly, research has indicated possible association between specific
markers in DAO and DAOA and more homogenous patient groups, e.g. association between markers M23
and M24 in Europeans. Given their function, and the fact that genetic variation in these genes is unlikely
to occur without any effect, DAO and DAOA remain plausible candidate genes for schizophrenia. However,
confirmation of this hypothesis can not be made on the basis on the available data but will require further
analyses.
DISC1
Personal communication from Dr David Porteous (Centre for Genomic and Experimental Medicine,
Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital,
Crewe Road, Edinburgh, UK).
Authoritative investigator rating: 4.5
PGC schizophrenia PI mean rating: 2.7
Disrupted in Schizophrenia 1 (DISC1) is an archetypal positional candidate gene, disrupted by a balanced
t(1;11) translocation that is linked, with genome-wide significance, to schizophrenia alone (LOD = 3.6)
and to schizophrenia plus related mental illness (MLOD = 7.1) in a large Scottish family 35,36. Thus, the
DISC1 locus meets the primary genetic criterion for candidature and merits biological validation. DISC1
encodes a scaffold protein regulating neuronal proliferation, migration, integration and signaling, spine
formation and synapse maintenance-neurobiology that aligns well with current concepts in
schizophrenia 37. Moreover, DISC1 protein binding partners, including PDE4B, PCM1 and NDE1, are
independently implicated as genetic risk factors for schizophrenia and related major mental illness
through cytogenetics, copy number variation and linkage (reviewed in 38). Rare DISC1 amino acid
substitution variants have been reported in schizophrenia 39, recurrent major depressive disorder,
segregating with psychiatric disorder 40 and autism 41. In contrast, meta-analysis of common DISC1 SNPs
has found no evidence of genome-wide significant association with schizophrenia 42 and DISC1 does not
appear on the GWAS list of significant associations for schizophrenia 43. The absence of evidence from
4
GWAS is, of course, not evidence of absence of effect; while GWAS can identify ancient variants common
to all populations, variants that are moderate to rare and/or population-specific and/or disorder
subtype-specific for illness will fall below the accepted level of genome wide significance. A further
limitation of GWAS and many CNV studies is that they do not identify functional variants directly. In this
regard, structure-function analysis of DISC1 has proved fruitful, demonstrating biological pleiotropy and
epistasis that is hidden from current GWAS analysis 44. There is good evidence from human 45,46 and
mouse 47 studies that modulation of DISC1 expression affects systems level changes in biologically
relevant pathways and clinical endophenotypes. Amino acid substitution polymorphisms and rare
variants have been shown experimentally to modulate structural and oligomerisation properties of DISC1
and to modulate or abrogate relevant biological traits, including -catenin signaling, ATF4-dependent
stress response and mitochondrial trafficking 48-51. Thus, DISC1 is analogous to the examples of APP and
PSEN1 and 2 in Alzheimer’s disease 52; risk genes that may score low on GWAS criteria, but high on rare
variant criteria do offer valuable and direct etiological insight into psychiatric disorders. Score = 4.5/5
(genome wide significant by linkage; functional genetic variants and biological evidence for relevance).
DRD2
Personal communication from Drs James Kennedy and Clement Zia (Centre for Addiction and Mental
Health, University of Toronto, Toronto, Ontario, Canada).
Authoritative investigator rating: 4
PGC schizophrenia PI mean rating: 4.1
One of the top hits in the most recent Psychiatric Genomics Consortium GWAS meta-analysis of
schizophrenia is rs2514218, located approximately 50kb upstream of DRD2. There is substantial
neurobiological evidence supporting a role of the dopamine D2 receptor in schizophrenia, most notably
the fact that all efficacious antipsychotic medications have significant D2 antagonism (Seeman et al,
1975). Furthermore, schizophrenia patients show elevated striatal D2 levels (e.g., SPECT 53) as well as D2
receptor super-sensitivity 54,55. These findings collectively suggest that rs2514218 and/or correlated
variants in regulatory sites may create elevated risk for schizophrenia by giving rise to higher D2
receptor expression. While rs2514218 does not appear to have a strong functional role based on ENCODE
data 56-58, molecular studies using tissues from specific brain regions will clarify the molecular
mechanisms of this genome-wide significant association. Interrogation of DRD2 regulatory sites for
possible association with the increased striatal D2 levels in schizophrenia patients may be useful.
D2 receptor occupancy is correlated with therapeutic efficacy for antipsychotics 59. Putative functional
single-nucleotide polymorphisms in DRD2 have been implicated in antipsychotic response (rs1799732/141C insertion/deletion 60) and side effects including rs1800497/TaqIA in tardive dyskinesia 61,62 and
rs6277/C957T 63 in antipsychotic-induced weight gain. However, association findings of these and other
DRD2 markers in the diagnosis of schizophrenia have been mixed 64, suggesting that the role of D2 in the
etiopathophysiology of schizophrenia may be modulatory rather than directly causative. Interestingly,
ZNF804A, another one of the top hits in the PGC2 GWAS meta-analysis, may regulate the expression of
DRD2 in addition to other schizophrenia candidate genes 65. Given this observation as well as the
complexity of D2-mediated signaling, further DRD2 gene-based studies as well as gene-gene interaction
and pathway analyses are required to decipher the role of DRD2 in schizophrenia. Based on its welldocumented therapeutic role, we can be cautiously optimistic that DRD2 may become one of the more
meaningful GWAS hits in terms of translational impact.
DRD3
Personal communication from Dr Michael Owen (Cardiff University, Cardiff, Wales, UK).
Authoritative investigator rating: 2
PGC schizophrenia PI mean rating: 2.3
5
This was an excellent functional candidate gene for schizophrenia given its role in pharmacology and its
location in the brain. In the light of what we know now about the genetic architecture of schizophrenia,
the initial studies and even the several meta-analyses that we, and others, conducted were
underpowered. The updated results of meta-analysis of candidate gene studies in SZGene and the
findings from PGC2 provide no support for the hypothesis that common genetic variants in this gene
confer risk of schizophrenia.
DTNPB1
Personal communication from Dr Brien Riley (Virginia Institute of Psychiatric and Behavioral
Genetics, Virginia Commonwealth University, Richmond, VA, USA).
Authoritative investigator rating: 2
PGC schizophrenia PI mean rating: 2.4
The score is based on the following rationale. If a “1” signifies a locus for which there has never been any
credible support (i.e., null expectation), there is some evidence for a locus in this region of chr 6 in family
studies and it does not seem to me, although this is intuitive rather than empirical, that the chr 6p signal
is being driven by the HLA region signal, although it is certainly possible. However, the pattern of
different haplotypes associated in almost every sample examined strongly suggests that there is no
stable association signal detectable at this locus in European samples. I think this is also the answer to
the publication pattern question: the focus in the early days of association studies was on any signal from
a locus of interest with very little attention paid to whether the specific signal observed was consistent
(i.e., really represented replication).
HTR2A
Personal communication from Drs Jiang Li and Herbert Y. Meltzer (Northwestern University,
Feinberg School of Medicine).
Authoritative investigator rating: 4
PGC schizophrenia PI mean rating: 2.3
Three HTR2A polymorphisms, rs6311, rs6313, rs6314, have been widely investigated in association
studies with schizophrenia. rs6311 (-1438G>A), located in the promoter region of HTR2A, is in strong
linkage disequilibrium with rs6313 (102T>C), a synonymous mutation. rs6314 (His452Tyr), the most
common missense variant, is located at the C-terminal region. It has been implicated in binding of
accessory/scaffolding proteins as well as G protein-coupled receptor desensitization and internalization
66. rs6313, a silent substitution, has been controversially associated with schizophrenia 67-75. It has been
associated with a subgroup of schizophrenia patients characterized by poor long-term outcome and
poor response to typical antipsychotic drugs 76. Prepulse inhibition and habituation has been reported to
be modulated by rs6311/rs6313 in schizophrenia, suggesting alterations in brain HTR2A may
contributes to the prepulse inhibition deficits present in some patients with schizophrenia. It conferred
an increased risk for psychosis in a meta-analysis of Alzheimer dementia subjects 77. These studies
support the conclusion that rs6311/rs6313 may contribute to an endophenotype characterized by poor
treatment response to clozapine, Only Arranz et al. reported positive finding with regard to clozapine
response in association with rs6311/rs6313 78,79. Others cannot replicate their findings 80-85. A metaanalysis of the association between HTR2A polymorphisms and clozapine response showed a deviation
from theoretically expected pattern in the funnel plots where studies should converge with increasing
sample size, suggesting a possibility of publication bias. The weighted mean of the odds ratios of all
studies on HTR2A genotypes including rs6311/rs6313/rs6314 was 1.7, thus, predicting only a minor
influence of this gene on clozapine response86.
rs6314 has been associated with hippocampal volume 87 and novelty processing in humans 88. It has been
shown to predict poor response to the atypical antipsychotic drug, clozapine, in some 78-80,89, but not all
studies 82-84. A recent study examined evidence from functional imaging and clinical data and reported
6
that rs6314 is associated with prefrontal function and response of negative symptoms to olanzapine, a
clozapine-like atypical antipsychotic drug 90. Functional studies have suggested that rs6314 may impact
on calcium signaling and mobilization as well as on reduced activation of phospholipases C and D,
resulting in markedly reduced intracellular signaling capacity 91,92. An in silico-based bioinformatics
analysis predict that rs6314 alters patterns of splicing with possible effects on HTR2A expression 90.
Based on an early study of allelic expression imbalance (AEI) in 23 adult brain tissue heterozygous for
rs6313, Bray et al. asserted that the HTR2A locus does not contain common variants affecting mRNA
levels in adult brain 93. However, Smith et al. recently combined in vitro gene-reporter assay and AEI
analysis with next-generation sequencing technology to show that significant AEI can be observed only in
the extended form of HTR2A harboring rs6311, but not in any mature mRNA transcripts. The
translational efficiency of long UTR is higher than short UTR, suggesting that rs6311 decreases usage of
an upstream transcription start site encoding a longer 5’UTR with greater translational efficiency 94.
According to postmortem prefrontal cortex samples from BrainCloud 95, promoter SNP rs6311(LD with
rs6313) is also a methylation QTL for HTR2A as it is highly correlated with CpG methylation at the HTR2A
across ethnicity 94, further suggesting potential epigenetic effect of this polymorphism on gene
expression. In conclusion, the common functional variants including rs6311, rs6313 and rs6314 of
HTR2A make a limited but definite contribution to the risk of schizophrenia and treatment response to
clozapine. Controversial results warrant more extensive investigation. Further study should focus on the
association with endophenotypes instead of a complex disease trait alone, or treatment response in
general, as the biological and pharmacological background influencing those traits could be largely
heterogeneous. Further study should also focus on the interaction between the genetic variants and
environmental factors in the context of the association with schizophrenia or drug response. With
increased sample size, not only common variants, but also rare mutations should also be included in
analysis to determine the accumulated genetic burden in conferring the risk for the disease or
endophenotypes.
NRG1
Personal communication from Dr Amanda Law (University of Colorado, Denver, CO, USA).
Authoritative investigator rating: 3
PGC schizophrenia PI mean rating: 2.9
Neuregulin 1 (NRG1) is an essential neurotrophin, a critical mediator of neurodevelopment, synaptic
plasticity and neocortical function and one of the most researched candidate susceptibility genes for
schizophrenia. NRG1 maps to 8p21-p12, a chromosomal region with prior evidence of genome-wide
linkage to schizophrenia 96-98. Association to common genetic variation in NRG1 and schizophrenia was
first reported in the landmark study of Stefansson and colleagues, in 2002 99, whereby genome-wide
linkage scans, extensive fine mapping and association analyses of extended Icelandic pedigrees identified
a 290kb risk haplotype in the 5’ region of NRG1 (HAPICE); a finding confirmed in Scottish 100 and Irish 101
populations. Subsequent association has been validated in three separate meta-analyses 102-104. Since the
original report, 30 independent studies have reported significant association to common NRG1 variants
(most notably complex haplotypes) and schizophrenia in European, Asian and African populations 12.
While NRG1 did not show significant association in the current SZGene meta-analysis 12, more recent
updates list NRG1 as positive 12 and recent analyses of three European genome-wide data sets provide
support for association of NRG1 HAPICE and additional novel haplotypes with schizophrenia 105.
Nevertheless, it is important to note that the associated haplotype or variants are not always HAPICE, (a
finding likely related to population heterogeneity), no obviously pathogenic mutations or copy number
variations have been identified in NRG1 and several negative studies exist12,106.
In addition to statistical associations, the evidence in favor of NRG1 as a schizophrenia risk gene is
strengthened by biological findings. First, risk polymorphisms in NRG1 are associated in humans with
multiple neurobiological phenotypes relevant to schizophrenia, including cognitive function, prefrontal
7
cortical physiology, and neocortical development 107-109. Second, neurobiological roles of NRG1 are
relevant to the disease process of schizophrenia, including key roles in neuronal migration,
neurotransmitter function, cortical inhibitory circuit development and myelination 106. Third, NRG1 gene
expression is altered in the brain of patients with schizophrenia and related to risk polymorphisms 110112; and fourth, mutation of NRG1 in rodents produces abnormalities in several behavioral domains
relevant to schizophrenia, including learning, memory, cognitive function and sociability 99,113-115.
Interestingly, genetic manipulations in mice 99,113-115 demonstrate that ‘overexpression’ or ‘knockdown’ of
the NRG1 gene leads to similar schizophrenia-related behaviors, suggesting a non-linear, inverted-U
model of NRG1 signaling and schizophrenia, an observation which may have important implications for
genetic association studies.
Even so, despite multiple positive reports of clinical association, the distinct neurobiological relevance of
NRG1’s functions to neurodevelopment and cortical function, and identification of potential biological
mechanisms of risk, large genome-wide association studies of schizophrenia have failed to provide
corroborative evidence of association to NRG1. Lack of support from this approach raises several
important questions regarding the validity of pre-GWAS genetic associations to NRG1; challenges
whether NRG1 is a reliable, disease-relevant genetic factor for schizophrenia, and raises the issue of
whether current GWAS single-marker association approaches are capable of identifying association to
complex genetic loci. It would be only pragmatic to conclude that the current data are inconclusive as to
whether NRG1 is a significant genetic risk factor for schizophrenia. However, failure to find association to
NRG1 in current schizophrenia GWAS may relate to several factors, including: limitations of singlemarker analysis; noting that the majority of previous associations to NRG1 are to complex and diverse
haplotypes, not single nucleotide variants 99-104,106; heterogeneity; noting that original isolation of the
gene was in small, relatively homogenous populations 99-101 and heterogeneity within the 1.2Mb, vastly
complex gene 106 has been shown to be pervasive within and across larger populations 104,106; geneenvironment interactions; noting the significant interaction of NRG1 with environmental risk variables,
including obstetric complications, psychosocial stress and cannabis 116,117, and finally gene-gene
interactions; noting variant interactions between NRG1 and genes in the neureuglin signaling pathway to
increase risk 108,118. Despite the failure of current GWAS to confirm association to NRG1, previous data
support critical roles for NRG1 in neurodevelopmental and neurobehavioral functions relevant to
schizophrenia. The ‘pre’- ‘post-GWAS’ validity conundrum will only likely resolve for NRG1 with the
application of multifactorial methods for GWAS data analysis which account for association in the context
of genetic background, genetic interplay and environmental modification.
RGS4
Personal communication from Dr Karoly Mirnics (Vanderbilt University, Nashville, KY, USA).
Authoritative investigator rating: 2
PGC schizophrenia PI mean rating: 2.1
Based on the current golden standards, the evidence that RGS4 sequence variants predispose to
schizophrenia is weak. However, this does not mean that RGS4 is not important for the disease
pathophysiology. These two categories should be always considered separately as a gene that has no
sequence variant predisposing toward a disease can be still critical for the overall progression of
pathology and emergence of symptoms. RGS4, just like most of the initial schizophrenia candidate genes,
did not show positive association in GWA studies (including BDNF, COMT, RELN and others), but the
evidence for their involvement in the disease progression and schizophrenia-associated endophenotypes
can be considered very strong. The following genetic studies support RGS4 as a schizophrenia
susceptibility gene 119-129. The following candidate gene studies (in addition to GWAS) do not support the
notion that sequence variants of RGS4 predispose to schizophrenia 130-139. The pathophysiological
evidence supporting a role for RGS4 in schizophrenia include:
1) Decreased RGS4 brain transcript expression in schizophrenia 140-143
8
2)
3)
4)
5)
6)
7)
8)
9)
10)
Decreased RGS4 brain protein expression in schizophrenia 144
Plausibility of biological effects – regulation of GPCR signaling 145-150
Genetic association/DNA methylation with suicide attempts in schizophrenia 119
Converging “hub” gene and interaction with other schizophrenia susceptibility genes 121,151-156
Cortical thickness associated with genotype 125
Brain connectivity associated with genotype 157
Working memory/cognitive performance associated with genotype 120,158-160
Medication efficacy depending on genotype 161,162
Antipsychotic treatment increases RGS4 membrane expression 163
9
Supplementary Figures
Figure S1. PGC SCZ mega-analysis vs. SZGene candidate gene meta-analysis
For each gene, the x-axis is the –log10(P) from the SZGene meta-analysis and the y-axis is the –log10(P)
from the PGC mega-analysis for a 25 kb window encompassing the gene. The data points are sized and
colored by the number of pre-GWAS candidate gene studies as reported in Table 1. The horizontal line
indicates the genome-wide significance threshold (5x10-8).
10
Figure S2. Gene ratings from 24 schizophrenia geneticists
The x-axis labels indicate the gene being rated as a risk factor for schizophrenia and the y-axis indicates
the distribution of ratings. The vertical length of a colored bar represents the proportion of investigators
giving a particular rating to that gene. The rating color scheme is in the legend on the right. The ratings
were a summary judgment of the current status of a gene as a genetic risk factor for schizophrenia
(1=very unlikely and 5=very likely). On the far left, “equal distribution reference” provides a reference
bar size for equal distribution amongst raters for a given gene. The absence of a particular colored bar
indicates that none of the investigators gave that rating for a gene.
11
Supplemental Tables
Table S1. Results for 59 markers in/near 25 schizophrenia candidate genes
Gene
Marker
Studies
Ncase
AKT1
APOE
BDNF
rs3730358
.2/3/4
270C/T
rs6265
rs28531779
rs737865
rs165599
rs4680
rs3918346
rs947267
rs778294
rs3916967
rs3916965
rs778293
rs1421292
rs3918342
rs2391191
rs1322784
rs1000731
rs999710
rs6675281
rs3738401
rs821616
rs1800497
rs1799732
rs1801028
rs6280
rs4646983
rs2619528
rs909706
rs2619522
rs2619538
rs1018381
rs2005976
rs760761
rs2619539
rs1011313
rs3213207
rs2228595
2
15
7
9
2
6
8
28
5
6
6
8
9
9
9
10
11
6
6
7
8
9
9
10
10
16
44
3
6
7
7
7
9
9
10
10
11
13
3
2543
1549
1242
2397
861
4552
5359
7622
1364
1524
3334
3574
4058
4348
4712
3968
5083
3297
3412
3608
3896
4705
4705
1228
3457
4160
6031
406
3370
4081
4101
4332
4227
4761
4560
5451
5385
6305
1227
CHRNA7
COMT
DAO
DAOA
DISC1
DRD2
DRD3
DRD4
DTNBP1
GRM3
SZG OR
(95% CI)
1.01 (0.91-1.13)
0.99 (0.82-1.20)
0.68 (0.52-0.87)
0.95 (0.87-1.04)
0.97 (0.72-1.30)
1.00 (0.95-1.06)
1.00 (0.95-1.05)
1.00 (0.96-1.05)
1.00 (0.89-1.12)
1.05 (0.95-1.16)
0.96 (0.89-1.03)
1.00 (0.94-1.07)
0.95 (0.90-1.01)
1.00 (0.94-1.06)
1.02 (0.97-1.08)
0.99 (0.94-1.05)
0.97 (0.92-1.02)
0.99 (0.92-1.07)
1.06 (0.98-1.14)
1.07 (1.00-1.14)
1.03 (0.95-1.12)
1.05 (0.99-1.12)
1.00 (0.94-1.06)
0.90 (0.79-1.03)
0.92 (0.82-1.02)
0.85 (0.71-1.03)
1.03 (0.97-1.08)
1.13 (0.76-1.67)
1.01 (0.93-1.09)
1.04 (0.97-1.10)
1.01 (0.93-1.08)
1.01 (0.95-1.07)
1.04 (0.93-1.15)
0.95 (0.89-1.02)
0.97 (0.90-1.04)
1.04 (0.99-1.10)
1.12 (1.02-1.23)
1.10 (1.02-1.19)
1.21 (0.96-1.52)
SZG P
0.82
0.95
0.0028
0.29
0.82
0.96
0.99
0.92
0.94
0.33
0.22
0.97
0.11
0.93
0.37
0.80
0.26
0.81
0.12
0.045
0.48
0.095
0.93
0.14
0.12
0.10
0.33
0.56
0.89
0.29
0.88
0.80
0.51
0.17
0.37
0.12
0.015
0.015
0.099
PGC OR
(95% CI)
1.02 (0.99-1.06)
0.99 (0.96-1.02) †
1.01 (0.97-1.06) †
0.95 (0.92-0.97)
1.01 (0.96-1.05)
0.98 (0.96-1.01)
1.00 (0.99-1.03)
0.99 (0.97-1.01)
1.03 (1.00-1.05)
0.99 (0.97-1.01)
1.00 (0.98-1.03)
1.00 (0.98-1.02)
1.00 (0.98-1.02)
1.01 (0.99-1.03)
1.00 (0.98-1.02)
1.00 (0.98-1.02)
1.00 (0.98-1.02)
1.00 (0.98-1.03)
1.02 (0.99-1.04)
1.01 (0.99-1.03)
0.98 (0.95-1.01)
1.00 (0.97-1.02)
1.00 (0.98-1.03)
1.00 (0.98-1.03)
No data
0.95 (0.89-1.03)
0.99 (0.97-1.01)
No data
0.97 (0.94-0.99)
1.01 (0.99-1.03)
1.03 (1.00-1.06)
1.00 (0.98-1.03)
0.99 (0.96-1.03)
0.97 (0.95-1.00)
0.97 (0.95-1.00)
0.99 (0.97-1.01)
0.99 (0.96-1.03)
1.04 (1.01-1.08)
1.01 (0.97-1.06)
12
PGC P
0.17
0.48
0.55
8.0e-5
0.79
0.17
0.29
0.56
0.035
0.30
0.82
0.88
0.96
0.53
0.81
0.77
0.92
0.82
0.22
0.29
0.13
0.68
0.76
0.88
0.22
0.31
0.019
0.35
0.020
0.74
0.72
0.022
0.021
0.32
0.78
0.012
0.58
PGC Pmin
±25kb
3.0e-4
0.0095
8.0e-5
PGC SNPs
±25kb
330
195
279
0.0096
0.0065
540
419
0.00040
0.015
390
360
0.00095
1652
8.3e-9
369
0.015
0.0026
0.0073
403
287
574
1.0e-10
677
HTR2A
KCNN3
MTHFR
NOTCH4
NRG1
PPP3CC
PRODH
RGS4
SLC6A3
SLC6A4
TNF
ZDHHC8
rs6311
rs6313
1333T/C
rs1801131
rs1801133
rs367398
rs6994992
rs62510682
rs35753505
rs7837713
rs383964
rs10917670
rs951439
rs2661319
rs951436
VNTR
5-HTTVNTR
5-HTTLPR
rs1800629
rs175174
7
26
1
8
11
5
6
6
13
1
4
7
7
8
9
6
9
15
7
4
2717
6384
184
1964
2529
1045
3999
4192
5874
1870
1453
4377
4519
4827
5049
731
1951
2652
1081
1461
1.14 (1.06-1.23)
0.98 (0.93-1.03)
1.12 (0.33-3.76)
0.91 (0.84-0.99)
1.09 (1.01-1.17)
1.00 (0.87-1.15)
1.06 (0.99-1.13)
0.94 (0.88-1.01)
0.95 (0.90-1.01)
0.99 (0.81-1.21)
1.09 (0.88-1.35)
0.94 (0.89-0.99)
0.97 (0.91-1.03)
0.93 (0.88-0.99)
1.01 (0.96-1.07)
0.97 (0.82-1.16)
1.11 (1.01-1.21)
1.01 (0.94-1.09)
1.00 (0.86-1.17)
1.00 (0.90-1.11)
0.0005
0.40
0.86
0.031
0.026
0.99
0.087
0.074
0.076
0.91
0.42
0.033
0.28
0.013
0.73
0.77
0.024
0.75
0.98
0.96
1.01 (0.99-1.04)
1.01 (0.99-1.04)
0.95 (0.93-0.98) †
1.02 (1.00-1.05)
1.01 (0.98-1.03)
No data
1.01 (0.98-1.03)
0.97 (0.95-1.00)
1.00 (0.97-1.02)
1.01 (0.97-1.06)
1.02 (0.97-1.07)
1.00 (0.97-1.02)
1.00 (0.97-1.02)
1.01 (0.99-1.03)
1.01 (0.99-1.03)
0.98 (0.94-1.01) †
0.91 (0.86-0.96) †
1.03 (1.00-1.07) †
0.91 (0.89-0.94)
0.98 (0.96-1.01)
0.18
0.18
3.3e-5
0.030
0.55
0.61
0.024
0.69
0.62
0.41
0.66
0.67
0.47
0.38
0.24
4.2e-4
0.058
5.6e-10
0.17
(rs12704290)
0.011
444
6.8e-6
0.016
713
443
1.1e-18
0.0012
560
4586
0.00017
0.0092
0.0061
387
445
238
0.0103
4.2e-4
497
207
1.7e-18
4.1e-6
294
314
We obtained the SZGene 164 database (http://www.szgene.org) in 11/2009 (active work on SZGene stopped in 12/2011). We selected all study for the 25
genes in Table 1 that met inclusion criteria: (a) case/control design, (b) published before 2009 (we verified that no GWAS were included), (c) subjects of
European ancestry, (d) biallelic markers and complete data. We selected markers that had been in ≥5 studies. If a gene did not have a marker with ≥5
studies, we selected the marker with the largest number of studies so that all 25 genes had at least one genetic marker. We conducted a fixed-effect metaanalysis for each marker. The first six columns show characteristics derived from SZGene. Gene=standard gene name. Marker=name of genetic variant
(converted to rs IDs where possible). Studies=SZGene studies that met inclusion criteria. Ncase=sum of cases. SZG OR=odds ratio (OR) and 95% confidence
interval (CI) from the SZGene meta-analysis. SZG P=meta-analysis P-value. The next four columns show results from the PGC schizophrenia megaanalysis. 165 PGC OR=OR and 95% CI. PGC P= P-value. PGC Pmin=minimum P-value ±25 kb of a gene. PGC SNPs=SNPs ±25 kb of the gene. Alleles were
harmonized between SZGene and PGC so that the ORs are comparable. The PGC and SZGene results are mostly for the same SNP but, for markers that
were not SNPs (†), all PGC SNP results within a range encompassing the variant were obtained, and the one with smallest P-value is shown (BDNF
270C/T, SLC6A3 VNTR, SLC6A4 5-HTTLPR, SLC6A4 5-HTTVNTR, APOE rs429358/rs7412, and KCNN3 1333T/C).
13
Table S2. Independent meta-analyses for historical genes published 2008-2014
Gene
PMID
rSID
Year
Lead Author
OR
P
Note
AKT1
19931325
rs3730358
2010
Lee
1.02 (0.94-1.12)
NS
Pooled across multiple ancestries
AKT1
23747160
rs3730358
2013
Loh
1.004(0.926–1.090)
0.92
Pooled across multiple ancestries
AKT1
18715757
rs3730358
2008
Shi
0.951 (0.854–1.060)
0.36
EUR
BDNF
23438165
270C/T
2013
Watanabe
1.20 (0.93–1.55)
0.16
EUR
COMT
19329282
rs737865
2009
Okochi
1.041 (0.978-1.108)
0.21
Pooled across multiple ancestries
COMT
19329282
rs165599
1.032 (0.960-1.108)
0.40
Pooled across multiple ancestries
COMT
19329282
rs4680
0.989 (0.942-1.039)
0.67
Pooled across multiple ancestries
COMT
20488458
rs4680
2011
Costas
0.947 (0.904-0.993)
0.023
Only over-dominant model reported
DAOA
21443574
rs2391191
2011
Muller
CI includes 1.0
NS
Only forest plot presented
DAOA
24447945
rs2391191
2014
Tan
0.96 (0.89-1.04)
0.30
EUR, random effects model
DAOA
24447945
rs947267
0.97 (0.87-1.09)
0.63
EUR, fixed effects model
DAOA
24447945
rs3918342
1.03 (0.92-1.15)
0.64
EUR, random effects model
DISC1
21483435
rs6675281
0.93
EUR
DISC1
21483435
rs3738401
0.11
EUR
DISC1
21483435
rs821616
0.51
EUR
DRD2
22370928
rs1801028
2012
Liu
1.47 (1.18-1.83)
0.0006
Pooled across multiple ancestries
DRD3
18295456
rs6280
2008
Ma
1.017 (0.943-1.097)
0.67
EUR
HTR2A
23857788
rs6313
2012
Jianliang
1.06 (0.96-1.17)
NS
Chinese
HTR2A
24962835
rs6313
2014
Tan
0.994 (0.903-1.093)
0.89
EUR, random effects model
HTR2A
23404241
rs6313
2013
Gu
1.12 (1.05-1.20)
0.28
EUR
MTHFR
21185933
rs1801131
2011
Peerbooms
1.06 (0.99-1.15)
NS
Pooled across multiple ancestries
MTHFR
24535549
rs1801133
2014
Nishi
1.16 (1.03-1.31)
0.014
Japanese, fixed effects model
MTHFR
24938371
rs1801133
2014
Hu
1.07 (0.98–1.16)
0.14
EUR, random effects model
MTHFR
24938371
rs1801131
1.07 (0.96–1.19)
0.22
EUR, random effects model
NRG1
19362450
rs6994992
1.03(0.97–1.10)
0.33
Pooled across multiple ancestries
NRG1
19362450
rs35753505
1.02(0.92–1.11)
0.76
Pooled across multiple ancestries
NRG1
19362450
rs62510682
1.06(0.98–1.15)
0.12
Pooled across multiple ancestries
2012
2009
Mathieson
Gong
ZDHHC8
20661937
rs175174
2010
Xu
0.97 (0.88-1.07)
0.55
EUR, fixed effects model
We searched PubMed for: ("schizophrenia"[MeSH Terms] OR "schizophrenia"[All Fields]) AND ("meta-analysis"[Publication Type] OR "meta-analysis as topic"[MeSH
Terms] OR "meta-analysis"[All Fields]). All studies 2008-2014 were obtained. NS=not significant at 0.05.
14
Table S3. Candidate gene studies of DAO
Paper
Bass et al, 2009
Ancestry
3 of 4 grandparents were of
English, Irish, Welsh, or
Scottish descent
Canadian, Russian
Phenotype
schizophrenia
Sample size
431 cases
442 controls
Variant
rs3741775, rs3918346,
rs2111902
P-value (OR)
n.s.
schizophrenia
Korean
homicidal behaviors in
schizophrenia
Corvin et al, 2007
Irish origin, i.e., Irish parents
/ grandparents
schizophrenia
373 cases, 812 controls
Fallin et al, 2005
Ashkenazi
274 trios
Gaysina et al, 2010
UK, Canada
schizophrenia,
schizoaffective
disorder
bipolar I disorder
bipolar disorder
rs3741775, rs3918346,
rs2111902, MDAAO-1 (SNP),
MDAAO-2 (SNP), MDAAO-3
(SNP), rs3918347, rs888531
rs2070586, rs2070587,
rs2070588, rs2111902,
rs3918346, rs3741775,
rs3825251
rs3741775, rs888531
rs3918346
rs2111902
rs2070587, rs2070588,
rs3741775, rs3825251,
rs3918346
5 SNPs typed
rs3741775
four SNP markers were associated in Canadian
samples
Chung et al, 2007
213 (Canadian cases)
241 (Canadian controls)
183 (Russian cases)
183 (Russian controls)
188 cases
Jönsson et al, 2009
Danish, Norwegian, Swedish
schizophrenia
rs2070587, rs2070588,
rs3741775, rs3825251
n.s.
Kim et al, 2010
Korean
schizophrenia
rs2070588, rs3741775,
rs3825251, rs3918346,
rs2111902, rs3220845
rs2070586
n.s.
Chumakov et al,
2002
337 trios
515 cases (UK)
1316 controls (UK)
385 cases (Canada)
312 controls (Canada)
420 cases (Denmark)
1004 controls (Denmark)
162 cases (Norway)
177 controls (Norway)
255 cases (Sweden)
292 controls (Sweden)
96 cases
96 controls
rs2070587
Liu et al, 2004
Chinese
schizophrenia
547 cases
536 controls
Liu et al, 2006
Taiwanese
schizophrenia
218 families
Ohnuma et al, 2009
Japanese
schizophrenia
340 cases
340 controls
Ohnuma et al, 2010
Japanese population
schizophrenia
Papagni et al, 2011
native English speakers
regional activation and
functional connectivity
1656 cases
1842 controls
121 subjects
rs3918347
rs2070587, rs2070588,
rs3825251, rs3918346,
rs2111902
rs3741775
rs2111902, rs3918346,
rs3741775
rs4964762, rs11114083,
rs2070586, rs2111902,
rs3918346, rs3741775,
rs11114086, rs11114087,
rs3825251, rs3918347,
rs4964770
rs3825251, rs3918347,
rs4964770
rs3918346
15
n.s.
n.s.
0.0034 (OR 1.43)
0.018 (OR 1.29)
n.s.
highly suggestive (any SNP or haplotype p <0.01)
n.s.
0.005 (allelic, females)
0.014 (genotypic, females)
0.025 (allelic, males)
0.002 (allelic, females)
0.005 (genotypic, females)
0.018 (allelic females)
n.s.
0.000001 (OR 1.59)
n.s.
n.s.
n.s.
Cases with one or two copies of the T allele showed
lower deactivation in the left precuneus and greater
Prata et al, 2008
Roussos et al, 2011
Caucasian with at least 3
grandparents born in
Scotland
Greek
in schizophrenia,
bipolar I, controls
bipolar affective
disorder
activation in the right posterior cingulate gyrus
213 cases, 197 controls
rs2111902, rs3918346,
rs3741775, rs3918347
n.s.
sensorimotor gating,
working memory,
personality in healthy
males
530 individuals
rs2111902, rs3918346,
rs3741775, rs3825251
rs4623951
n.s.
Sacchetti et al, 2013
Italian
schizophrenia
391 patients,488 controls
Schumacher et al,
2004
German
bipolar affective
disorder
schizophrenia
300 cases, 300 controls
schizophrenia
Stefanis et al, 2007
Caucasian, Indian, Native
American, Asian, African,
and mixed ethnicity
Greek
113 nuclear families
168 cases
168 controls
2243 young male military
conscripts
Suliman et al, 2010
German
schizophrenia
Shinkai et al, 2007
schizotypy and
cognitive
endophenotypes
299 cases, 300 controls
531 cases
755 controls
Vilella et al, 2007
Spanish
schizophrenia
589 cases
617 controls
Wirgeres et al, 2008
Norwegian
155 patients
Wood et al, 2007
self-reported whites from
various US regions
PANSS in
schizophrenia
schizophrenia
345 schizophrenia cases
150 schizoaffective cases
352 controls
rs2070586, rs2070587,
rs2111902, rs10861974,
rs3741775, rs3918347
MDAAO4, MDAAO5, MDAAO6
MDAAO4
MDAAO5
MDAAO6
rs3741775, rs3918346,
rs2111902, rs3918347
n.s.
0.026 (allelic)
0.019 (allelic),
0.041 (genotypic)
0.021 (allelic)
n.s.
rs2111902
rs3918346
rs3741775
n.s.
0.033 (d´-S2B working memory)
0.048 (perceptual aberration scale CAPE, depression)
rs987044, rs3916982,
rs7136681, rs73410945,
rs7980427, rs11114086,
rs3825251, STR-1-dao2, STR2-dao3, SNP-3-exon11,
rs10746135, rs7313861,
rs3918305
rs11114071
rs4964766
rs2070586
rs73193464
rs2111902
rs3918346
rs3741775
rs4623951, rs11114086,
rs2070587, hCV2880411,
rs4964281
rs2070588, rs3741775
rs2070587
rs3741775, rs17041020,
rs4623951
rs2070586
n.s.
rs2111902
16
0.015 (adjusted p-value, PPI 85_30)
0.004 (adjusted p-value, PPI 85_60)
0.004 (adjusted p-value, pooled PPI 60 ms)
n.s.
0.04
0.049
0.015
0.017
0.021
0.039
0.046
n.s.
n.s.
0.036 (PANSS total score)
n.s.
0.02159 (SCZ vs CON, allelic)
0.01219 (SCZ+SCA vs CON, allelic)
0.03973 (SCZ+SCA vs CON, genotypic)
0.00219 (SCZ vs CON, allelic)
0.00667 (SCZ vs CON, genotypic)
0.00056 (SCZ+SCA vs CON, allelic)
0.00192 (SCZ+SCA vs CON, genotypic)
rs3918346
rs3825251
Yamada et al, 2005
Central Japan
schizophrenia
50 cases
52 controls
IVS1a+465G>C
IVS1b+15G>A
570 cases
570 controls
(sample set B)
IVS1a+465G>C,
IVS1b+15G>A,
DAO-01, DAO-02, DAO-03,
DAO-04, DAO-05
DAO-06
124 families
Yang et al, 2013
Taiwan Han Chinese
Table S2 Citations
ratio of D-Serine to
total Serine
schizophrenia
Sustained attention
was assessed using
the unmasked and
masked CPTs (Zd´
and Zmd´)
Four CPT strata
50 cases
52 controls
912 cases, 600 controls
IVS1a+465G>C,
IVS1b+15G>A, DAO-01, DAO02, DAO-03, DAO-04, DAO05, DAO-06
DAO-01, DAO-02, DAO-03,
DAO-04, DAO-05, DAO-06
rs2070585, rs2070587
rs11114083
rs2070586
rs55944529
0.00068 (SCZ vs CON, allelic)
0.00297 (SCZ vs CON, genotypic)
0.00004 (SCZ + SCA vs CON, allelic)
0.00028 (SCZ + SCA vs CON, genotypic)
0.01800 (SCZ vs CON, allelic)
0.04340 (SCZ vs CON, genotypic)
0.00246 (SCZ+SCA vs CON, allelic)
0.00647(SCZ + SCA vs CON, genotypic)
0.038 (genotypic)
0.041 (allelic)
0.026 (genotypic)
n.s.
0.020 (case-control, allelic)
0.023 (case-control, genotypic)
n.s.
n.s.
n.s.
0.0357 (raw p-value, allele-based, Zmd´ >= -2.5)
0.0293 (raw p-value, trend-based, Zmd´>= -2.5)
0.0491 (raw p-value, genotype-based, Zd´>= -2.5)
0.0275 (raw p-value, allele-based, Zmd´ >= -2.5)
0.0252 (raw p-value, trend-based, Zmd´>= -2.5)
0.0459 (raw-p-value, genotype-based, overall)
0.0313 (raw p-value, allele-based, overall)
0.0299 (raw p-value, trend-based, overall)
0.0392 (raw p-value, allele-based, Zd´ < -2.5)
0.0365 (raw p-value, trend-based, Zd´ < -2.5)
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Corvin A, McGhee KA, Murphy K, Donohoe G, Nangle JM, Schwaiger S, Kenny N, Clarke S, Meagher D, Quinn J, Scully P, Baldwin P, Browne D, Walsh C, Waddington JL, Morris DW, Gill M.
Evidence for association and epistasis at the DAOA/G30 and D-amino acid oxidase loci in an Irish schizophrenia sample. Am J Med Genet B Neuropsychiatr Genet. 2007 Oct
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Fallin MD, Lasseter VK, Avramopoulos D, Nicodemus KK, Wolyniec PS, McGrath JA, Steel G, Nestadt G, Liang KY, Huganir RL, Valle D, Pulver AE. Bipolar I disorder and schizophrenia: a 440single-nucleotide polymorphism screen of 64 candidate genes among Ashkenazi Jewish case-parent trios. Am J Hum Genet. 2005 Dec;77(6):918-36.
Gaysina D, Cohen-Woods S, Chow PC, Martucci L, Schosser A, Ball HA, Tozzi F, Perry J, Muglia P, Kennedy JL, King N, Vincent JB, Parikh SV, Strauss J, Craig IW, McGuffin P, Farmer A.
Association analysis of DAOA and DAO in bipolar disorder: results from two independent case-control studies. Bipolar Disord. 2010 Aug;12(5):579-81.
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Jönsson EG, Saetre P, Vares M, Andreou D, Larsson K, Timm S, Rasmussen HB, Djurovic S, Melle I, Andreassen OA, Agartz I, Werge T, Hall H, Terenius L. DTNBP1, NRG1, DAOA, DAO and
GRM3 polymorphisms and schizophrenia: an association study. Neuropsychobiology. 2009;59(3):142-50.Ohnuma T, Shibata N, Maeshima H, Baba H, Hatano T, Hanzawa R, Arai H.
Association analysis of glycine- and serine-related genes in a Japanese population of patients with schizophrenia. Prog Neuropsychopharm Biol Psychiatry. 2009 Apr 30;33(3):511-8.
Kim B, Kim H, Joo YH, Lim J, Kim CY, Song K. Sex-different association of DAO with schizophrenia in Koreans. Psychiatry Res. 2010 Sep 30;179(2):121-5.
Liu X, He G, Wang X, Chen Q, Qian X, Lin W, Li D, Gu N, Feng G, He L. Association of DAAO with schizophrenia in the Chinese population. Neurosci Lett. 2004 Oct 21;369(3):228-33.
Liu YL, Fann CS, Liu CM, Chang CC, Wu JY, Hung SI, Liu SK, Hsieh MH, Hwang TJ, Chan HY, Chen JJ, Faraone SV, Tsuang MT, Chen WJ, Hwu HG. No association of G72 and D-amino acid
oxidase genes with schizophrenia. Schizophr Res. 2006 Oct;87(1-3):15-20.
Ohnuma T, Shibata N, Baba H, Ohi K, Yasuda Y, Nakamura Y, Okochi T, Naitoh H, Hashimoto R, Iwata N, Ozaki N, Takeda M, Arai H. No association between DAO and schizophrenia in a
Japanese patient population: a multicenter replication study. Schizophr Res. 2010 May;118(1-3):300-2.
Ohnuma T, Shibata N, Maeshima H, Baba H, Hatano T, Hanzawa R, Arai H. Association analysis of glycine- and serine-related genes in a Japanese population of patients with schizophrenia.
Prog Neuropsychopharmacol Biol Psychiatry. 2009 Apr 30;33(3):511-8.
Papagni SA, Mechelli A, Prata DP, Kambeitz J, Fu CH, Picchioni M, Walshe M, Toulopoulou T, Bramon E, Murray RM, Collier DA, Bellomo A, McGuire P. Differential effects of DAAO on regional
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Prata D, Breen G, Osborne S, Munro J, St Clair D, Collier D. Association of DAO and G72(DAOA)/G30 genes with bipolar affective disorder. Am J Med Genet B Neuropsychiatr Genet. 2008
Sep 5;147B(6):914-7.Corvin A, Donohoe G, McGhee K, Murphy K, Kenny N, Schwaiger S, Nangle JM, Morris D, Gill M. D-amino acid oxidase (DAO) genotype and mood symptomatology
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Sacchetti E, Scassellati C, Minelli A, Valsecchi P, Bonvicini C, Pasqualetti P, Galluzzo A, Pioli R, Gennarelli M. Schizophrenia susceptibility and NMDA-receptor mediated signalling: an
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Schumacher J, Abou Jamra R, Becker T, Klopp N, Franke P, Jacob C, Sand P, Fritze J, Ohlraun S, Schulze TG, Rietschel M, Illig T, Propping P, Cichon S, Deckert J, Nöthen MM. Investigation of
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Shinkai T, De Luca V, Hwang R, Müller DJ, Lanktree M, Zai G, Shaikh S, Wong G, Sicard T, Potapova N, Trakalo J, King N, Matsumoto C, Hori H, Wong AH, Ohmori O, Macciardi F, Nakamura J,
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Suliman H, Schumacher J, Becker T, Cichon S, Schulze TG, Propping P, Rietschel M, Nöthen MM, Jamra RA. Association study of 20 genetic variants at the (D)-amino acid oxidase gene in
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Vilella E, Costas J, Sanjuan J, Guitart M, De Diego Y, Carracedo A, Martorell L, Valero J, Labad A, De Frutos R, Nájera C, Moltó MD, Toirac I, Guillamat R, Brunet A, Vallès V, Pérez L, Leon M, de
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18
Table S4. Candidate gene studies of DAOA
Paper
Addington et al, 2004
Andreou et al, 2012
Bakker et al, 2007
Bass et al, 2009
Ancestry
mixed
Caucasian
patients had at least three
Dutch-born Caucasian
grandparents
three of the grandparents
were of English, Irish,
Welsh, or Scottish descent
Phenotype
childhood-onset schizophrenia
and psychosis NOS
Sample size
98 children and
adolescents
5-HIAA, HVA, and MHPG
concentration in cerebrospinal
fluid in healthy individuals
132 individuals
deficit and non-deficit
schizophrenia
308 cases
580 controls
schizophrenia
431 cases
442 controls
bipolar disorder
303 cases
442 controls
734 cases
442 controls
225 individuals
301 cases
604 controls
139 cases (116
´enriched cases´
(linkage to 13q33),
113 controls
Bousman et al, 2013
Australian
schizophrenia and bipolar
disorder combined
transition to psychosis in
individuals at ultra-high risk for
psychosis
Carrera et al, 2010
Spanish Caucasian origin
schizophrenia
Chen et al, 2004
US birth, self-reported as
´white´
bipolar affective disorder
Chen et al, 2013
Chinese
schizophrenia
454 cases
480 controls
Chen et al, 2012
Chinese
resting-state brain activity in
major depression
488 cases
480 controls
Chiesa et al, 2011
Korean
Chiesa et al, 2012
Korean
Chumakov et al, 2002
Canadian, Russian
schizophrenia, treatment
outcomes
major depressive disorder
(MDD), bipolar disorder (BD)
221 cases
145 cases (MDD)
132 cases (BD)
170 controls
213 (Canadian cases)
241 (Canadian
controls)
183 (Russian cases)
183 (Russian controls)
19
Variant
rs746187, rs3916964, rs778294, rs778293,
rs1935062, rs1935058
rs2391191
rs3916967
rs2391191, rs778294
P-value (OR)
n.s.
rs3918342
0.03 (5-HIAA)
0.001 (HVA)
0.004 (HVA)
n.s.
rs1421292
rs3918342, rs2391191, rs3916967, rs1421292
rs3916965, rs3916967, rs2391191, rs947267,
rs778294, rs778293, rs1421292
rs3918342
rs2391191, rs947267, rs778294, rs1421292,
rs1341402, rs1935062, rs954581
rs3918342
rs3918342
rs1421292
rs7320588, rs6416389, rs1935057, rs1341402,
rs2391191, rs1539070, rs1935062, rs6491961,
rs7986339, rs2153674, rs7989006, rs7984976,
rs947267, rs778294, rs778293, rs3918342
rs9586843, rs7329966, rs7324448, rs1575633,
rs1570709
rs1935058, rs2391191, rs954581
rs1935062
rs947267
rs3916965, rs3916966, rs3916967, rs2391191,
rs3918341, rs9558562, rs947267, rs778294,
rs3918342, rs1421292
rs3916965, rs3916966, rs3916967, rs9558562,
rs947267, rs3918342, rs1421292
rs2391191
rs3918341
rs778294
rs3916966, rs3916967, rs2391191, rs3916968,
rs778293
rs7139958
rs9558571
rs3916966, rs3916967, rs2391191, rs3916968,
rs7139958, rs9558571, rs778293
DAOA_M06 (SNP), rs746187 (M07),
DAOA_M08 (SNP), DAOA_M09 (SNP),
DAOA_M10 (SNP), rs3916964 (M11),
rs3916966 (M13), rs3918341 (M16),
DAOA_M17 (SNP), rs947267 (M18), rs778294
(M19), rs3916971 (M21), rs3916970 (M20)
rs3918342 (M23)
0.031
0.015
n.s.
n.s.
0.016
n.s.
0.038
0.008
0.044
n.s.
n.s.
n.s.
0.0072 (OR 1.67)
0.0048 (enriched, OR 1.77)
0.0403 (all cases, OR 0.69)
0.0295 (enriched cases, OR 0.66)
n.s.
n.s.
0.01 (allelic OR 1.27)
0.04 (OR 1.09)
0.02 (1.37)
n.s.
0.005 PANSS positive at baseline)
0.008 (allelic, PANSS at baseline)
n.s.
n.s.
0.019 (allelic, Canadian)
rs2391191 (M15)
rs778293 (M22)
rs3916967 (M14)
rs3916965 (M12)
rs1421292 (M24)
Chung et al, 2007
Korean
Corvin et al, 2007
Irish
Corvin et al, 2007
Irish origin, i.e., Irish
parents / grandparents
Dalvie et al, 2010
mixed ancestry,
Caucasian
Detera-Wadleigh et al,
2006
various ethnicities
homicidal behaviors in
schizophrenia
depression/anxiety factor in
schizophrenia
schizophrenia
188 cases
bipolar 1: age at onset, #
depressive episodes, #
hospitalizations for depression
schizophrenia and bipolar
disorder
191 cases
schizophrenia
bipolar disorder
196 schizophrenia, 59
schizoaffective
373 cases, 812
controls
meta-analysis
meta-analysis
meta-analysis
Di Maria et al, 2009
Italian descent
psychosis
185 Alzheimer´s
disease
Donohoe et al, 2007
Irish
episodic memory
93 cases
Fallin et al, 2005
Ashkenazi
schizophrenia / schizoaffective
disorder
274 trios
rs3918341, rs9301030, rs3916968, rs947267,
rs701567, rs778294
rs3918346
0.01
rs778293, rs3918342, rs1421292
rs2391191
rs3916965
rs701567
n.s.
0.01 (corrected p-value, OR 1.31)
0.005 (corrected p-value, OR 1.34)
n.s.
rs746187, rs3916964, rs1341402, rs3916967,
rs3918341, rs947267, rs778294, rs954581,
rs3916970, rs3916971
rs3916965
rs3916966
rs1935058
rs2391191
rs1935062
rs778293
rs3918342
rs1421292
rs746187, rs3916964, rs3916966, rs1935058,
rs1341402, rs3916967, rs3918341, rs1935062,
rs947267, rs778294, rs954581, rs3916970,
rs3916971
rs3916965
rs2391191
rs778293
rs3918342
rs1421292
rs746187, rs3916964, rs3916965, rs3916966,
rs1935058, rs1341402, rs3916967, rs2391191,
rs3918341, rs947267, rs778294, rs954581,
rs3916970, rs3916971, rs778293, rs1421292
rs1935062
rs3918342
rs1341402, rs1341403, rs6491961, rs9558571,
rs778294, rs12864685
rs2153674
rs2391191
n.s.
rs2391191, rs947267, rs778294, rs3916970,
rs3916968, rs1935062, rs954580, rs2893229,
rs1341406, rs1341402, rs701567,
DAOA_GCintronic, DAOA_3'UTR873,
20
0.017 (allelic, Russian)
0.032 (allelic, Canadian)
0.003 (allelic, Canadian)
0.007 (genotypic, Canadian)
0.038 (allelic, Canadian)
0.007 (allelic, Canadian)
0.020 (genotypic, Canadian)
0.019 (allelic, Canadian)
0.044 (genotypic, Canadian)
0.006 (genotypic, Russian)
n.s.
0.0001
0.0413
0.0015
0.0000
0.0143
0.0003
0.0000
0.0010
n.s.
0.0002
0.0006
0.0033
0.0006
0.0092
n.s.
0.0019
0.0309
n.s.
0.033
0.028 (immediate recall)
0.015 (delayed recall)
gene is suggestive (any SNP or
haplotype minimal p value
0.01<p<0.05)
DAOA_3'UTR1746
Gawlik et al, 2010
Gaysina et al, 2010
Goldberg et al, 2006
Gomez et al, 2008
Grigoroiu-Serbanescu
et al, 2010
Hall et al, 2004
Hall et al, 2008
Hattori et al, 2003
bipolar I disorder
337 trios
14 SNPs
German Caucasian
descent
UK, Canada
affective psychosis
Americans of European
extraction (Caucasian
according to self report)
schizophrenia, cognitive
variables
248 cases
188 controls
515 cases (UK)
1316 controls (UK)
385 cases (Canada)
312 controls (Canada)
up to 106 trios
>600 subjects
(cognitive function)
14 normal individuals
(fMRI)
30 normal individuals
(fMRI)
rs3916966, rs1935058, rs2391191, rs1935062,
rs947267, rs3918342, rs9558575
rs3916965, rs12584489, rs2391191,
rs1935062, rs947267, rs778292, rs3918342,
rs1421292
rs9558562
M01, M02, M03, rs2391191 (M04), rs1935058
(M05), rs1935062 (M06), rs778294 (M07), M08,
M09, M10, M11
M10
646 nuclear families
rs1341402, rs12874006, rs1539070,
rs9284226, rs2153674, rs9558567, rs947267,
rs3918342
rs2391191
rs3918341
rs1935062
rs3916965, rs1935057, rs1341402, rs3916967,
rs2391191, rs1935062, rs67705083, rs778294,
rs954581, rs3916971, rs778293, G72_z6:1117,
rs3918342, rs1421292
rs778293
rs3916965
rs1935057
rs3916967
rs2391191
M7, M12, M14, M23, M25
M15
rs3918342, rs1421292
Hungarian
Romanian
South African Afrikaner,
USA
Scottish
bipolar disorder
juvenile onset mood disorders
bipolar I global diagnosis,
psychotic bipolar I subtype
198 cases
180 controls
bipolar I with delusions
bipolar I in non-psychotic
123 cases
38 cases
schizophrenia
169 South African trios
210 USA trios
61 individuals
hippocampal function in
subjects at high risk of
schizophrenia
bipolar disorder
22 multiplex families
21
rs1998654, rs2181953, rs978714, rs1359387,
M-13, rs2391191, rs947267, rs954581,
rs778334, rs2012887, M-23
rs1815686
rs1935058
rs1341402
rs1935062
rs778294
suggestive (any SNP or haplotype
minimal p value 0.01<p<0.05)
n.s.
n.s.
0.05 (UK sample)
n.s.
0.03 (genotypic, continuous
performance test)
0.04 (genotypic, n-back [one back]
working memory test)
0.05 (genotypic, verbal paired
associate learning)
fMRI: strong effect on BOLD
activation in hippocampus during
episodic memory paradigm
n.s.
0.025
0.029
0.026
n.s.
0.042 (dominant model)
0.044 (OR 1.82)
0.037 (OR 1.88)
0.043 (OR 1.82)
0.043 (OR 1.82)
n.s.
0.045 (S African trios; n.s. US trios
differences in the activation of the
left hippocampus and parahippocampus in the contrast of
sentence completion versus rest,
and in recruitment of right inferior
prefrontal cortex in relation to
increasing task difficulty
n.s.
0.041
0.00077
0.0075
0.0078
0.018
Hong et al, 2006
Hukic et al, 2013
Chinese
Swedish
schizophrenia
cognitive manic symptoms
(CMS) in bipolar I disorder
152 families (NIMH
pedigrees)
216 families
488 cases
1044 controls
rs1935058, rs1341402, rs2391191, rs1935062,
rs947267, rs778294, rs954581
rs947267
rs3916967
rs2391191
Jansen et al, 2009
European descent
cognitive functions
423 healthy individuals
rs1935062
rs3918342
rs1421292
Jansen et al, 2010
Jönsson et al, 2009
European descent
Danish, Norwegian,
Swedish
memory encoding, retrieval
schizophrenia
Korostishevsky et al,
2004
Ashkenazi
schizophrenia
Korostishevsky et al,
2006
Kotaka et al, 2009
Palestinian Arab
Japanese
Krug et al, 2011
western- or middle
European descent
Li et al, 2007
various ethnicities
schizophrenia
methamphetamine induced
psychosis
brain activation in right middle
temporal gyrus during verbal
fluency task
schizophrenia (meta-analysis)
83 healthy subjects
420 cases (DK), 1004
controls (DK), 162
cases (Norway), 177
controls (Norway), 255
cases (Sweden), 292
controls (Sweden)
60 cases
130 controls
56 families from
northern Israel
136 families from
central Israel
31 families from
southern Israel
209 cases
291 controls
rs3918342, rs1421292
rs2391191, rs778294, rs3918342,
M9924634108M24
rs3916965, rs3916967, rs2391191, rs3918341,
rs947267, rs778294, rs3916970
rs3918342
rs778293
rs3916971
rs3916966
rs3916965, rs3916966, rs3916967, rs2391191,
rs3918341, rs947267, rs778294 , rs3916971,
rs778293, rs3918342
rs3916970
rs3916965, rs2391191, rs947267, rs3918342,
rs1421292
rs778293
96 healthy individuals
rs3918342, rs1421292
2138 cases, 2228
controls, 463 parentoffspring trios
rs3916966, rs3916967, rs3918341, rs947267,
rs778294, rs3916970, rs3916971, rs778293,
rs1935062
rs3916965
rs2391191
rs3918342
rs1421292
rs3916965, rs3916966, rs3916967, rs2391191,
rs947267, rs778294, rs3916970, rs3916971,
rs778293, rs3918342, rs3916968
rs3916965, rs3916967, rs2391191
rs778294
rs3918342
rs778293
Liu et al, 2006
Taiwanese
schizophrenia
218 families
Ma et al, 2006
Han Chinese, Scottish
schizophrenia
588 (Han Chinese
cases) 588 (Han
Chinese controls)
183 (Scottish cases)
182 (Scottish controls)
22
n.s.
0.016
0.018 (CMS vs. Non-CMS)
0.026 (CMS vs controls)
0.039 (CMS vs. Non-CMS)
0.019 (CMS vs controls)
n.s.
0.002 (letter-number-span test)
0.001 (d2-test for attention)
0.001 (letter-number-span test)
0.001 (d2-test for attention)
n.s.
n.s.
n.s.
0.001 (genotypic)
0.001 (allelic)
0.005 (genotypic)
0.04 (genotypic)
0.04 (genotypic)
n.s.
0.018 (haplotype relative risk,
northern Israel)
0.014 (transmission disequilibrium
test, northern Israel)
n.s.
0.0015 (allelic)
0.00016 (genotypic)
rs1421292 positively correlated with
brain activation in right middle
temporal gyrus and right procuneus
n.s.
0.0225 (OR 1.12)
0.0086 (OR 1.15)
0.0136 (OR 0.88)
0.0010 (OR 0.8)
n.s.
n.s.
0.025 (OR 0.69, Scottish sample)
0.0005 (OR 0.60, Scottish)
0.022 (OR 0.71, Scottish)
0.0013 (OR 0.76, Han Chinese)
Ma et al, 2009
Chinese
Maheshwari et al,
2009
Caucasian
126 family trios
bipolar disorder
19 families with 146
samples from
Statistical Explanation
for Positional Cloning
(STEPC) analysis
376 bipolar parentproband trios
555 cases, 564
controls
Mössner et al, 2010
Mulle et al, 2005
Müller et al, 2011
German
samples from NIMH
Genetics Initiative and the
Western Psychiatric
Institute and Clinic at the
University of Pittsburgh
Canadian
progression of prodromal
syndromes to first episode
psychosis
82 probands
schizophrenia
159 trios
rs778294
rs3918342
rs778293
rs1935058
rs1341402
rs9301030
rs1815686
rs12862108
rs1935062
rs778294
rs778326
rs978714, rs2025522, rs3916964, rs9558551,
rs7981258, rs9301029, rs1253464, rs3916965,
rs9519671, rs3916966, rs1935057, rs1935058,
ss107796322, rs1341402, rs2391191,
ss107796323, ss107796324, rs12862108,
rs9301030, rs1935062, rs9519683,
ss104807115, rs7986339, rs947267, rs701567,
rs778294, rs7987770, ss107796325,
rs9558581, rs778326, rs954581, rs9301034,
rs778336, rs778334, rs778293, rs2012887,
rs3918342, rs1421292
variants identified by sequencing DAOA exons:
ss104807091, ss104807092, ss104807093,
ss104807094, ss104807095, ss104807096,
ss104807097, ss104807098, ss104807099,
ss104807100, ss104807101, ss104807102,
ss104807103, rs2391191, ss104807104,
ss104807105, ss104807106, ss104807107,
rs9558562, ss104807108, ss104807109,
ss104807110, ss104807111, ss104807112,
ss104807113, rs9519683, ss104807114,
ss104807115, ss104807116, ss104807117,
ss104807118, rs9582999, ss104807119,
ss104807120, rs9670704, ss104807121,
ss104807122, ss104807123, rs778294,
ss104807124, ss104807125, ss104807126,
ss104807127, ss104807128, ss104807129,
ss104807130, ss104807131, rs9558573,
ss104807132, ss104807133, ss104807134,
ss104807135, ss104807136
rs1935058, rs2391191, rs1935062, rs947267,
rs778293, rs3918342, rs1421292
rs1341402
rs778294
M-1, M-2, M-3, M-5, M-11, M-12, M-13, M-14,
M-15, M-16, M-21, M-22, M-23, M-24
M-4
n.s.
0.02 (all)
(all), 0.041 (male)
0.0009
0.0083
0.031
0.039
0.020
0.0074
0.017
0.026
n.s.
No significant excess of rare
variants in cases compared to
controls
n.s.
0.002
0.030
n.s.
0.04
bipolar disorder
303 core families
rs1341402, rs2391191, rs947267, rs778294
rs1935062
n.s.
0.02 (total sample)
bipolar disorder with psychotic
symptoms
157 families
rs1935062
0.01 (European sample)
n.s.
23
Ohi et al, 2009
Pae et al, 2010
Prata et al, 2008
Prata et al, 2012
Rethelyi et al, 2009
Rietschel et al, 2008
Japanese
Korean
bipolar disorder
meta-analysis
schizophrenia
meta-analysis
schizophrenia
antipsychotic response after
switch to aripiprazole
1774 (cases)
2092 (controls)
86 patients
rs1341402, rs2391191, rs1935062, rs947267,
rs778294
rs1341402, rs2391191, rs1935062, rs947267,
rs778294
rs2391191
rs3916965, rs3916967, rs2391191, rs778294,
rs3916970
rs778293
rs947267
rs3918342
rs746187, rs3916966, rs2391191, rs3916972
brain function during verbal
fluency
50 healthy volunteers
rs746187
Hungarian Caucasian
descent
German
schizophrenia
280 cases,
230 controls
500 major depression
patients, 1030 controls
rs2391191, rs3918342
schizophrenia
391 patients,
488 controls
Sanders et al, 2008
European ancestry
schizophrenia
1870 cases
2002 controls
Schulz et al, 2011
Caucasian
Schulze et al, 2005
German, Polish
reduced cortical thickness in
schizophrenia
bipolar disorder
52 patients,
42 controls
300 patients
(German), 300
controls (German),
294 patients (Polish),
24
0.019 (allelic)
0.005 (Schedule for the
Assessment of Negative Symptoms
[SANS] score)
0.02 (Brief Psychiatric Rating Scale
[BPRS] score)
n.s.
n.s.
213 bipolar I cases,
197 controls
Italian
0.03 (fixed effects model, East
Asians)
n.s.
0.034 (genotypic)
0.030 (allelic)
0.037 (allelic)
0.02 (Brief Psychiatric Rating Scale
[BPRS] score)
bipolar disorder
Saccetti et al, 2013
n.s.
rs3918342
rs1421292
rs2391191
Caucasian with at least 3
of 4 grandparents born in
Scotland
English native speakers
major depression, neuroticism
n.s.
Significant effect on activation in the
left postcentral and supramarginal
gyri (FWE p<0.05)
n.s.
rs3916965, rs1935058, rs1341402, rs3916967,
rs2391191, rs1935062, DAO_3UTR_SNP12,
rs3916971, rs3918342, rs1421292
rs778293
G72_z6:1117
n.s.
rs1341402, rs1341403, rs6491961, rs9558571,
rs778294
rs12864685
rs778294, rs3918342, rs2391191, rs778293,
rs3916968, rs3916967, rs3916966, rs3916965,
rs1421292, rs701567, rs778334, rs17713906,
rs10492528, rs12864685, rs12874006,
rs1935060, rs2039934, rs7139958, rs8002132,
rs9284226, rs9301030, rs9555175, rs9558573,
rs9670704, rs1361562, G72GD486 (SNP),
G72RS425 (SNP)(SNP rs identifiers from SZ
gene database)
rs1539070
rs1557072
rs2391191
n.s.
rs1341402, rs2391191
rs3918342
rs3918342
rs3918342
0.02 (major depression)
0.04 (major depression)
0.05 (recessive model)
n.s.
0.05 (OR 1.13)
0.02 (OR 1.84)
associated with distinct cortical
thinning
n.s.
<0.02 (bipolar disorder)
0.005 (bipolar with psychosis)
<0.0004 (bipolar with delusions)
Schumacher et al,
2004
Caucasian
schizophrenia
bipolar disorder
Schumacher et al,
2005
German descent
panic disorder
311 controls (Polish)
299 cases
300 controls
300 cases
300 controls
152 cases, 208
controls
Seifuddin et al, 2012
various ethnicities
bipolar disorder
meta-analysis
Shi et al, 2009
Han Chinese
schizophrenia
561 families
Shi et al, 2008
various ethnicities
schizophrenia
4304 cases, 5423
controls, 1384 families
(Meta-analysis)
rs1421292
rs1341402, rs1935062, rs778294
M23
rs2391191
M12
M24
M12, rs1341402, rs2391191, rs1935062,
rs778294, M24
M23
rs2391191, rs3916972
rs421292
rs778293
rs3918342
rs1421292, rs2391191, rs778294
rs3918342
rs947267
rs778293
rs3916965, rs3916966, rs1935058, rs1341402,
rs3916967, rs2391191, rs3918341, rs1935062,
rs778294, rs3916970, rs3916971, rs778293,
rs3918342, rs1421292
rs947267
rs778293
rs1421292
bipolar disorder
Shin et al, 2007
Korean
schizophrenia
Shinkai et al, 2007
Canadian population,
various ethnicities
schizophrenia
Soronen et al, 2008
Finnish
visuospatial ability in bipolar
disorder
1145 cases, 1829
controls, 174 families
388 patients, 367
controls
113 nuclear families,
168 cases, 168
controls
180 families
rs2391191, rs778294, rs1341402, rs1935058,
rs1935062
rs947267
rs778294
rs3916965, rs3916966, rs3916967, rs2391191,
rs3918341, rs3916970
rs3916971
rs947267, rs2391191, rs778293, rs3916967 ,
rs3916965, rs1421292, rs3916972
rs746187
rs3918342
rs3916966
rs2391191
25
<0.007 (bipolar delusions)
n.s.
0.033 (allelic), (OR 1.28)
0.037 (allelic), (OR 1.28)
0.048 (allelic), (OR 1.25)
0.036 (allelic), (OR 1.27)
n.s.
0.013 (allelic, OR 1.33)
0.025 (genotypic, OR 1.68)
n.s.
0.024 (OR 2.12, dominant)
0.031 (OR 1.39, allelic model)
0.049 (OR 1.35, allelic model)
0.047 (OR 1.35, allelic model)
n.s.
0.05 (OR 1.14)
n.s.
0.0012
n.s.
0.03 (OR 0.87, all), 5.62E-6 (OR
0.71, Asians)
0.0002 (OR 0.81, Asians)
0.027 (OR 1.11, all ethnicities)
0.031 (OR 1.12, Europeans)
n.s.
0.008
0.009
n.s.
0.03
n.s.
0.013 (OR 0.67, case-control)
0.029 (transmission disequilibrium
test)
0.0015 (General ability)
0.0010 (Abstraction)
0.0013 (Psychomotor speed)
4.00E-06 (Visuospatial ability)
0.0091 (Auditory attention)
0.0298 (Verbal working memory)
0.0047 (Immediate visual memory)
0.0005 (Delayed visual memory)
0.0032 (Free short delay recall)
0.0443 (Free long delay recall)
0.0173 (Recognition memory)
0.0162 (Stroop Interference score)
0.0195 (Semantic fluency)
0.0002 (General ability)
0.0003 (Abstraction)
Soronen et al, 2011
Finnish
Mood disorder (MOOD),
bipolar disorder, major
depressive disorder (MDD),
anxiety, alcoholism, psychotic
symptoms, suicide attempts,
more time ill
178 bipolar I and II
patients, 272 major
depressive disorder
patients, 1322 controls
rs2391191
rs778336
Stefanis et al, 2007
Greek
2243 male conscripts
rs2391191, rs778293, rs3918342
Tan et al, 2014
Caucasian, Asian
n.s.
Spanish
white persons from the
United Kingdom
rs746187, rs3916967, rs2391191, rs947267,
rs778293, rs1421292, rs2181953
rs3916965, rs2391191, rs778294, rs778293,
rs1421292, rs1935058, rs1341402, rs954581,
DAOA_3'UTR_SNP12
rs2391191, rs778294, rs778293, rs1421292,
rs1935058, rs954581,
rs391695
rs1341402
DAOA_3'UTR_SNP12
rs3916967, rs778293, rs3918342, rs1935062
rs2391191
n.s.
Williams et al, 2006
17515 cases, 25189
controls
589 cases
617 controls
709 cases
1416 controls
rs2391191, rs947267, rs3918342
Vilella et al, 2007
schizotypy and cognitive
endophenotypes
schizophrenia, bipolar
disorder, depressive disorder
schizophrenia
0.0034 (Psychomotor speed)
5.00E-06 (Visuospatial ability)
0.0088 (Auditory attention)
0.0213 (Verbal working memory)
0.0047 (Immediate visual memory)
0.0010 (Delayed visual memory)
0.0024 (Free short delay recall)
0.0206 (Free long delay recall)
0.0079 (Recognition memory)
0.0060 (Stroop Interference score)
0.0239 (Semantic fluency)
0.0086 (General ability)
0.0063 (Abstraction)
0.0369 (Phonemic fluency)
0.0083 (General ability)
0.0173 (Abstraction)
0.0125 (Psychomotor speed)
0.0108 (Visuospatial ability)
0.0047 (Stroop Interference score)
0.0168 (Semantic fluency)
0.0051 (General ability)
0.0392 (Visuospatial ability)
0.0465 (MOOD, all)
0.0310 (MOOD, all)
0.0209 (MOOD, positive FHx)
0.0406 (MDD, all)
0.0407 (MDD, positive FHx)
0.0447 (anxiety)
0.0114 (time ill)
n.s.
rs2153674
rs701567
rs954580
schizophrenia
bipolar I disorder
Wang et al, 2004
Han Chinese
schizophrenia
706 cases
1416 controls
537 cases
538 controls
rs3916965
Wood et al, 2007
self-reported whites from
various US regions
schizophrenia
345 schizophrenia
cases, 150
schizoaffective cases,
352 controls
Yang et al, 2013
Taiwan´s Han Chinese
Population
schizophrenia
912 cases, 600
controls
26
rs2391191, rs947267, rs3918342, rs1935062,
rs1935058, rs954580, rs1341402, rs9301036,
rs9301035, rs778336, rs778334, rs778332,
rs778331, rs778330, rs17713906, rs1642681,
rs1341401, rs11618600, rs10492527
rs3916966, rs45476401, rs113692101,
rs2391191, rs778294, rs9558573
n.s.
n.s.
0.047
0.03
0.01
n.s.
0.0010 (OR 1.33, all)
0.020 (OR 1.33, males)
0.021, OR 1.34, females)
0.019 (OR 1.23, all)
0.045 (OR 1.29, females)
n.s.
n.s.
Yue et al, 2006
Chinese Han descendants
schizophrenia (SZ), early
onset schizophrenia (EOS),
male schizophrenia
Yue et al, 2007
Han Chinese
schizophrenia (SZ), clinical
symptoms
Zhang et al, 2009
Chinese Han
bipolar disorder
Zuliani et al, 2009
UK population
bipolar disorder, temporal lobe
and amygdala structure
Zou et al, 2005
Han Chinese
216 cases, 321
controls (SZ), 88
cases, 131 controls
(EOS), 120 cases, 184
controls (men)
359 cases
359 controls
237 trios
475 cases,
588 controls
38 cases, 81 controls
233 trios
rs2391191, rs778294
n.s.
rs947267
0.006 (OR 1.43, SZ)
0.012 (OR 1.67, EOS)
0.034 (OR 1.45, males)
n.s.
0.004 (OR 1.38)
0.019 (, trios)
n.s.
0.047 (OR 0.77)
0.003 (OR 1.33)
rs1421292: decreased gray matter
density left temporal pole in bipolar
disorder. rs3918342: reductions in
right amygdala gray matter density
n.s.
0.0108
0.0018
rs2391191, rs778294, rs3918342
rs947267
rs3916965, rs2391191, rs3918342
rs778294
rs778293
rs1421292, rs3918342
rs3916967
rs2391191
rs3916965
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