The Pie of Schizophrenia
(Theoretical: Early Molecular Biology)
Mendelian Form 1 (.5%)
Mendelian Form 2 (1%)
Mendelian Form 3
(1.5%)
Major Locus 1 (8%)
Major Locus 2 (4%)
Polygenic (75%)
Phenocopies (10%)
The Pie of Schizophrenia
(Theoretical: Current)
Mendelian Form 1 (.5%)
Mendelian Form 2 (1%)
Mendelian Form 3
(1.5%)
Major Locus 1 (8%)
Major Locus 2 (4%)
Polygenic (75%)
Phenocopies (10%)
Table 23.1. Risks for schizophrenia in genetic
relatives of schizophrenics. Adapted from
Gottesman (1991, Figure 10).
Genetic Relation:
General Population
Type of relation:
Risk:
1%
Third-degree
Cousins
2%
Second-degree
Uncles/aunts
Nieces/nephews
Grandchildren
Half-siblings
2%
3%
4%
6%
First degree
Children
Parents
Siblings
DZ twins
13%
6%
9%
17%
Identical
MZ twins
48%
-2
-1
0
Schizophrenic
Schizotypal
Frequency
-3
1
2
3
1
2
3
2
3
2
3
2
3
Total Liability
-3
-2
-1
0
Specific Genetic Liability
-3
-2
-1
0
1
General Genetic Liability
-3
-2
-1
0
1
Specific Environmental Liability
-3
-2
-1
0
1
General Environmental Liability
General
Population
-3
-2
-1
0
Total Liability
1
2
Schizophrenic
Schizotypal
Frequency
Relatives of
Schizophrenics
3
4
25
24
23
22.1
21.1
21
22.1
22.3
Schematic of chromosome 6 giving two
potential linkage hotspots.
Summary of Linkage
Results in Schizophrenia
From Owen et al., Trends in Genetics (2005), 21, 518-525
Red lines = genome-wide significance
Blue lines = significant in more than 1 sample
Red arrow = possible chromosomal anomolies
Yellow = potential candidate genes
Summary of GWAS studies
in schizophrenia
GWAS genes of interest in schizophrenia
Replication
Replication
? Replication
Lee et al., Neuro & Biobeh Rev (2012)
“Whilst GWAS have identified new and novel
genes that are associated with SZ and BPD, the
extent of phenotypic variance that is explained by
these genes is disappointingly low.”
Lee et al., Neuro & Biobeh Rev (2012), p. 565
Summary of CNV studies
in schizophrenia
Summary of Results:
• 22q11 microdeletion --> velocardiofacial syndrome (VCFS)
aka DiGeorge syndrome; increased risk for mental retardation,
autism, bipolar disorder, and schizophrenia.
• only 6 good CNV studies as of 2010 but evidence for rare
CNV deletions in 1q21.1 and 15q13.3 which affect psychosis
and other behavioral problems
• strong effect, but account for about 1% percent of cases
Tam et al. (2009). Biol Psychiatry; Bassett et al. (2010) Am J Psychiat
Lee et al., Neuro & Biobeh Rev (2012), p. 565
Sometimes, CNVs are not
gene specific
Region
Gene
CNV
? Lession: Mucking something up in a region
is not good.
Lee et al., Neuro & Biobeh Rev (2012)
Example:
Lack of specificity for Schizophrenia
Often, range of psychopathology is even greater.
Summary of Results in Psychiatric Genetics:
(oversimplified)
• No single gene, Mendelian forms detected
(exception: mental retardation)
• Hardly any major loci found
• Few established phenocopies
• GWAS data suggest very polygenic
• Promising early results for CNVs
Notable Exceptions:
• Many Mendelian forms of mental retardation
• Major Loci: ALD and ALDH & Alcoholism
• Amphetamine psychosis = phenocopy for
schizophrenia
Odds ratios for ADHD & 7 repeat allele in DRD4
From 7 meta-analyses on European or mostly European Ancestry
But a summary of GWAS studies says:
“None of these [5] papers reports any associations that
are formally genome-wide significant after correction for
multiple testing.”
Franke, Neale, Faraone (2009). Genome-wide association
studies in ADHD. Human Genetics, 126:13-50
Frontiers:
Endophenotypes
Endophenotype:
(“within” phenotype)
A phenotype closer to gene action than
the phenotype of study; usually an
anatomical, physiological, or
biochemical variable.
Strategy of Endophenotypes:
Detect genes that influence the endophenotype instead
of genes for the disorder.
Examples for schizophrenia:
• Ventricular size
• Abnormal eye tracking
Frontiers:
Genes and Neuroimaging
Legend for the next two figures
From Heinz et al. (2004). Nature Neuroscience, 8, 20-21.
From Heinz et al. (2004). Nature Neuroscience, 8, 20-21.
From Heinz et al. (2004). Nature Neuroscience, 8, 20-21.
Legend for next Figure
From Hariri et al. (2005), Arch gen Psychiat 62:146-152
From Hariri et al. (2005), Arch gen Psychiat 62:146-152
From Hariri et al. (2005), Arch gen Psychiat 62:146-152
Frontiers:
Genes-environment
Interaction
From Caspi et al., Science 297-851-854
From Foley et al., Arch gen Psychiat, 61:738-744
Depression as a function of stressful life events and the short-long
polymorphism in the serotonin transporter gene
From Caspi et al., Science 301, 386-389
Frontiers:
Rare variants
Perhaps there are so many genes
involved in schizophrenia that new mutations
in several of these genes could replenish
the loss from selection.
Paraphrase of Erlenmeyer-Kimling lecture, c. 1972 trying to explain the paradox
of high heritability and low fitness in schizophrenia.
See Keller (2006) Brain & Behavioral Science.
Rare Variant Hypothesis:
• Could be mutations in a gene or CNVs
• Rare gene mutations hard to find in
GWAS.
• Need sequencing to find them.
Future Thought:
Perhaps behavior is the genetics of
behavior is so polygenic and complex
that the study of genetics is not the best
way to proceed.