Supplementary Table 3. Thirty-three additional candidate genes encoding proteins that could be directly placed in one or more of the three networks involved in ASDs (Figures 1-3).
These genes are implicated in ASDs through at least two independent lines of genetic evidence, including common genetic variants (identified through candidate gene association
studies) and/or rare gene variants (gene mutations and/or copy number variations (CNVs), i.e. deletions (del) and/or duplications (dup) in people with ASDs) and/or ‘other’ genetic
evidence (including gene expression studies, gene/protein function studies, and genetic animal studies).
Gene
CACNA1C
Locus
12p13.33
Common genetic variants
-
Mutations
mutation 1
CNVs *
del 2
CD44
CHD8
CNTNAP2
11p13
14q11.2
7q35-7q36.1
genetic association with ASDs 11,12
mutations 8,9
-
multiple deletions 3
del 10
del 13-16, dup 14,17
CTNNB1
3p22.1
-
mutation 9
-
CYP19A1
15q21.2
genetic association with ASDs 20,21**
-
ERK1
ESR1
ESR2
GATA1
16p11.2
6q25.1
14q23.2
Xp11.23
genetic association with ASDs 20
genetic association with ASDs 20,21 **
-
-
del 14
del 14, 17, 25-28
dup14-17,26-28
del 17,30
del 13, dup 2,17
GRIA1
5q33.2
-
-
-
GRIN1 (encodes NMDAR1)
GRIN2B (encodes NMDAR2B)
9q34.3
12p13.1
mutations9,35
dup 16
del 30
GRIK2
JARID1C
KCNMA1
6q16.3
Xp11.22
10q22.3
mutation 38
mutation 8
del 17,30 , dup 17
del 13
dup 11
MET
7q31.2
genetic association with ASDs 34
genetic linkage and association with
autism 21,36,37 **
genetic association with autism 39
repeated genetic association with
ASDs 40
-
del 2
Other genetic evidence
Cd44 is involved in cerebellar Purkinje cell loss 4; loss
of cerebellar Purkinje cell function is involved in the
etiology of autism 5-7
CTNNB1 expression is decreased in the postmortem
brain of autistic people 18; CTNNB-dependent
signalling is involved in ASD etiology 9,19
CYP19A1 expression is decreased in the postmortem
brain of people with autism 22; male Cyp19a1
knockout mice display severe deficits in social
recognition and memory that resemble symptoms of
ASDs 23,24
Esr1 regulates social interaction in male mice 29
Esr2 regulates social interaction in male mice 29
GRIA1 shows abnormal expression levels in
postmortem brains of autistic people 31 ; Gria1
knockout mice display ASD-like features 32
mice with reduced expression of Grin1 display
autism-like behaviour 33
decreased MET expression was found in postmortem
brain of autistic people 41
Supplementary Table 3 - continued.
Gene
Locus
Common genetic variants
Mutations
CNVs *
NQO2
6p25.2
-
-
NRXN1
NTRK1
2p16.3
1q23.1
genetic association with ASDs 21 **
genetic association with ASDs 20
mutation
-
dup 16
del 2,14-17,45-48,
dup 10,11
del 14
PARK2
6q26
-
-
del 14-17,46, dup 14,15
PLXNB1
PLXNB3
PTEN
3p21.31
Xq28
10q23.31
genetic association with ASDs 21 **
-
mutation 8
mutations9,50
del 13, dup 13,16
-
ROBO1
3p12.3-p12.2
genetic association with ASDs 21 **
-
dup 2,17
RORA
SCN2A
15q22.2
2q24.3
genetic association with autism 56,57
mutations8,58
del 53
-
SEMA3A
SLC1A2
(encodes EAAT2)
7q21.11
genetic association with ASDs 21 **
-
del 25
11p13
-
-
multiple deletions 3
SLC1A3
(encodes EAAT1)
5p13.2
-
-
-
STAR
8p11.23
-
-
STX1A
WNT2
7q11.23
7q31.2
genetic association with autism 65,66
genetic association with autism 69
-
dup 14
del 13, 67,
dup 13, 26,30,68
del 2
44
Other genetic evidence
Nqo2 knockout mice show improvements in spatial
learning and object recognition learning 42, which are
both impaired or altered in people with ASDs 23,43
Plxnb1 is involved in cerebellar Purkinje cell function
49
; loss of cerebellar Purkinje cell function is involved
in the etiology of autism 5-7
Pten regulates social interaction in mice 51
ROBO1 expression is reduced in lymphocytes of
autistic patients 52
RORA expression is decreased in the postmortem
brain of autistic people 54 ; Rora knockout mice
display autistic features 55
SEMA3A is involved in cerebellar Purkinje cell
function and loss 59,60 ; loss of cerebellar Purkinje cell
function is involved in the etiology of autism 5-7
SLC1A3 expression is increased in postmortem brain
of individuals with autism 31; Slc1a3 knockout mice
have social withdrawal symptoms 61
STAR expression is decreased in the postmortem brain
of autistic people 18 . STAR is involved in response to
social challenges, such as social isolation 62,63, which
itself is linked to developing autism-like behaviour 64
-
Abbreviations: ASD(s), autism spectrum disorder(s); GWAS, genome-wide association study; GWASs, genome-wide association studies, SNP(s), single nucleotide polymorphism(s).
*
Copy number variations (CNVs) that were either identified in people with ASDs through a genome-wide array-based hybridization approach 2,10,13-17,25-27,30,45,46,53 and/or are ‘recurrent’ in
that they were found in at least two unrelated people with ASDs 3,28,47,48,67,68.
** Using
homozygous haplotype mapping, a genetic approach aimed at detecting homozygous segments of identical haplotypes - each consisting of multiple SNPs - that are shared at a
(statistically significant) higher frequency amongst ASD patients compared to parental controls and are hence associated with ASDs, this gene was identified as an ASD candidate gene 21.
References
1. Splawski I, Timothy KW, Sharpe LM, Decher N, Kumar P, Bloise R et al. Ca(V)1.2 calcium channel
dysfunction causes a multisystem disorder including arrhythmia and autism. Cell 2004; 119: 19-31.
2. Marshall CR, Noor A, Vincent JB, Lionel AC, Feuk L, Skaug J et al. Structural variation of chromosomes
in autism spectrum disorder. Am J Hum Genet 2008; 82: 477-488.
3. Xu S, Han JC, Morales A, Menzie CM, Williams K, Fan YS. Characterization of 11p14-p12 deletion in
WAGR syndrome by array CGH for identifying genes contributing to mental retardation and autism.
Cytogenet Genome Res 2008; 122: 181-187.
4. Williams BL, Yaddanapudi K, Hornig M, Lipkin WI. Spatiotemporal analysis of purkinje cell degeneration
relative to parasagittal expression domains in a model of neonatal viral infection. J Virol 2007; 81: 26752687.
5. Whitney ER, Kemper TL, Bauman ML, Rosene DL, Blatt GJ. Cerebellar Purkinje cells are reduced in a
subpopulation of autistic brains: a stereological experiment using calbindin-D28k. Cerebellum 2008; 7:
406-416.
6. Whitney ER, Kemper TL, Rosene DL, Bauman ML, Blatt GJ. Density of cerebellar basket and stellate
cells in autism: evidence for a late developmental loss of Purkinje cells. J Neurosci Res 2009; 87: 22452254.
7. Martin LA, Goldowitz D, Mittleman G. Repetitive behavior and increased activity in mice with Purkinje
cell loss: a model for understanding the role of cerebellar pathology in autism. Eur J Neurosci 2010; 31:
544-555.
8. Neale BM, Kou Y, Liu L, Ma'ayan A, Samocha KE, Sabo A et al. Patterns and rates of exonic de novo
mutations in autism spectrum disorders. Nature 2012; 485: 242-245.
9. O'Roak BJ, Vives L, Girirajan S, Karakoc E, Krumm N, Coe BP et al. Sporadic autism exomes reveal a
highly interconnected protein network of de novo mutations. Nature 2012; 485, 246-250.
10. Girirajan S, Brkanac Z, Coe BP, Baker C, Vives L, Vu TH et al. Relative burden of large CNVs on a range
of neurodevelopmental phenotypes. PLoS Genet 2011; 7: e1002334.
11. Tan GC, Doke TF, Ashburner J, Wood NW, Frackowiak RS. Normal variation in fronto-occipital circuitry
and cerebellar structure with an autism-associated polymorphism of CNTNAP2. Neuroimage 2010; 53:
1030-1042.
12.
Scott-Van Zeeland AA, Abrahams BS, Alvarez-Retuerto AI, Sonnenblick LI, Rudie JD, Ghahremani D et
al. Altered Functional Connectivity in Frontal Lobe Circuits Is Associated with Variation in the Autism
Risk Gene CNTNAP2. Sci Transl Med 2010; 2: 56ra80.
13.
Rosenfeld JA, Ballif BC, Torchia BS, Sahoo T, Ravnan JB, Schultz R et al. Copy number variations
associated with autism spectrum disorders contribute to a spectrum of neurodevelopmental disorders.
Genet Med 2010; 12: 694-702.
14.
Pinto D, Pagnamenta AT, Klei L, Anney R, Merico D, Regan R et al. Functional impact of global rare
copy number variation in autism spectrum disorders. Nature 2010; 466: 368-372.
15.
Gai X, Xie HM, Perin JC, Takahashi N, Murphy K, Wenocur AS et al. Rare structural variation of synapse
and neurotransmission genes in autism. Mol Psychiatry 2012; 17: 402-411.
16.
Bremer A, Giacobini M, Eriksson M, Gustavsson P, Nordin V, Fernell E et al. Copy number variation
characteristics in subpopulations of patients with autism spectrum disorders. Am J Med Genet B
Neuropsychiatr Genet 2011; 156: 115-124.
17. Prasad A, Merico D, Thiruvahindrapuram B, Wei J, Lionel AC, Sato D et al. A discovery resource of rare
copy number variations in individuals with autism spectrum disorder. G3 (Bethesda) 2012; 2: 1665-1685.
18.
Chow ML, Pramparo T, Winn ME, Barnes CC, Li HR, Weiss L et al. Age-dependent brain gene
expression and copy number anomalies in autism suggest distinct pathological processes at young versus
mature ages. PLoS Genet 2012; 8:e1002592.
19. Zhang Y, Sun Y, Wang F, Wang Z, Peng Y, Li R. Downregulating the Canonical Wnt/beta-catenin
Signaling Pathway Attenuates the Susceptibility to Autism-like Phenotypes by Decreasing Oxidative
Stress. Neurochem Res 2012; 37:1409-1419.
20. Chakrabarti B, Dudbridge F, Kent L, Wheelwright S, Hill-Cawthorne G, Allison C et al. Genes related to
sex steroids, neural growth, and social-emotional behavior are a ssociated with autistic traits, empathy,
and Asperger syndrome. Autism Res 2009; 2: 157-177.
21. Casey JP, Magalhaes T, Conroy JM, Regan R, Shah N, Anney R et al. A novel approach of homozygous
haplotype sharing identifies candidate genes in autism spectrum disorder. Hum Genet 2012; 131: 565-579.
22. Sarachana T, Xu M, Wu RC, Hu VW. Sex Hormones in Autism: Androgens and Estrogens Differentially
and Reciprocally Regulate RORA, a Novel Candidate Gene for Autism. PLoS One 2011; 6: e17116.
23. Pierman S, Sica M, Allieri F, Viglietti-Panzica C, Panzica GC, Bakker J. Activational effects of estradiol
and dihydrotestosterone on social recognition and the arginine-vasopressin immunoreactive system in male
mice lacking a functional aromatase gene. Horm Behav 2008; 54: 98-106.
24. Wilson CE, Brock J, Palermo R. Attention to social stimuli and facial identity recognition skills in autism
spectrum disorder. J Intellect Disabil Res 2010; 54: 1104-1115.
25. Christian SL, Brune CW, Sudi J, Kumar RA, Liu S, Karamohamed S et al. Novel submicroscopic
chromosomal abnormalities detected in autism spectrum disorder. Biol Psychiatry 2008; 63: 1111-1117.
26. Sanders SJ, Ercan-Sencicek AG, Hus V, Luo R, Murtha MT, Moreno-De-Luca D et al. Multiple Recurrent
De Novo CNVs, Including Duplications of the 7q11.23 Williams Syndrome Region, Are Strongly
Associated with Autism. Neuron 2011; 70: 863-885.
27. Weiss LA, Shen Y, Korn JM, Arking DE, Miller DT, Fossdal R et al. Association between microdeletion
and microduplication at 16p11.2 and autism. N Engl J Med 2008; 358: 667-675.
28. Shinawi M, Liu P, Kang SH, Shen J, Belmont JW, Scott DA et al. Recurrent reciprocal 16p11.2
rearrangements associated with global developmental delay, behavioral problems, dysmorphism, epilepsy,
and abnormal head size. J Med Genet 2010; 47: 332-341.
29. Murakami G, Hunter RG, Fontaine C, Ribeiro A, Pfaff D. Relationships among estrogen receptor, oxytocin
and vasopressin gene expression and social interaction in male mice. Eur J Neurosci 2011; 34: 469-477.
30. Griswold AJ, Ma D, Cukier HN, Nations LD, Schmidt MA, Chung RH et al. Evaluation of Copy Number
Variations Reveals Novel Candidate Genes in Autism Spectrum Disorder Associated Pathways. Hum Mol
Genet 2012; e-pub ahead of print 22 May 2012.
31. Purcell AE, Jeon OH, Zimmerman AW, Blue ME, Pevsner J. Postmortem brain abnormalities of the
glutamate neurotransmitter system in autism. Neurology 2001; 57: 1618-1628.
32. Wiedholz LM, Owens WA, Horton RE, Feyder M, Karlsson RM, Hefner K et al. Mice lacking the AMPA
GluR1 receptor exhibit striatal hyperdopaminergia and 'schizophrenia-related' behaviors. Mol Psychiatry
2008; 13: 631-640.
33. Meyer U, Nyffeler M, Yee BK, Knuesel I, Feldon J. Adult brain and behavioral pathological markers of
prenatal immune challenge during early/middle and late fetal development in mice. Brain Behav Immun
2008; 22: 469-486.
34. Yoo HJ, Cho IH, Park M, Yang SY, Kim SA. Family based association of GRIN2A and GRIN2B with
Korean autism spectrum disorders. Neurosci Lett 2012; 512: 89-93.
35. O'Roak BJ, Deriziotis P, Lee C, Vives L, Schwartz JJ, Girirajan S et al. Exome sequencing in sporadic
autism spectrum disorders identifies severe de novo mutations. Nat Genet 2011; 43: 585-589.
36. Jamain S, Betancur C, Quach H, Philippe A, Fellous M, Giros B et al. Linkage and association of the
glutamate receptor 6 gene with autism. Mol Psychiatry 2002; 7: 302-310.
37. Holt R, Barnby G, Maestrini E, Bacchelli E, Brocklebank D, Sousa I et al. Linkage and candidate gene
studies of autism spectrum disorders in European populations. Eur J Hum Genet 2010; 18: 1013-1019.
38. Adegbola A, Gao H, Sommer S, Browning M. A novel mutation in JARID1C/SMCX in a patient with
autism spectrum disorder (ASD). Am J Med Genet A 2008; 146A: 505-511.
39. Laumonnier F, Roger S, Guérin P, Molinari F, M'rad R, Cahard D et al. Association of a functional deficit
of the BKCa channel, a synaptic regulator of neuronal excitability, with autism and mental retardation. Am
J Psychiatry 2006; 163: 1622-1629.
40. Campbell DB, Warren D, Sutcliffe JS, Lee EB, Levitt P. Association of MET with social and
communication phenotypes in individuals with autism spectrum disorder. Am J Med Genet. B
Neuropsychiatr Genet 2010; 153B: 438-446.
41. Campbell DB, D'Oronzio R, Garbett K, Ebert PJ, Mirnics K, Levitt P et al. Disruption of cerebral cortex
MET signaling in autism spectrum disorder. Ann Neurol 2007; 62: 243-250.
42. Benoit CE, Bastianetto S, Brouillette J, Tse Y, Boutin JA, Delagrange P et al. Loss of quinone reductase 2
function selectively facilitates learning behaviors. J Neurosci 2010; 30: 12690-12700.
43. Kourkoulou A, Leekam SR, Findlay JM. Implicit learning of local context in autism spectrum disorder. J
Autism Dev Disord 2012; 42: 244-256.
44. Iossifov I, Ronemus M, Levy D, Wang Z, Hakker I, Rosenbaum J et al. De novo gene disruptions in
children on the autistic spectrum. Neuron 2012; 74: 285-299.
45. Bucan M, Abrahams BS, Wang K, Glessner JT, Herman EI, Sonnenblick LI et al. Genome-wide analyses
of exonic copy number variants in a family-based study point to novel autism susceptibility genes. PLoS
Genet 2009; 5: e1000536.
46. Glessner JT, Wang K, Cai G, Korvatska O, Kim CE, Wood S et al. Autism genome-wide copy number
variation reveals ubiquitin and neuronal genes. Nature 2009; 459: 569-573.
47. Kim HG, Kishikawa S, Higgins AW, Seong IS, Donovan DJ, Shen Y et al. Disruption of neurexin 1
associated with autism spectrum disorder. Am J Hum Genet 2008; 82: 199-207.
48. Ching MS, Shen Y, Tan WH, Jeste SS, Morrow EM, Chen X et al. Deletions of NRXN1 (neurexin-1)
predispose to a wide spectrum of developmental disorders. Am J Med Genet B Neuropsychiatr Genet 2010;
153B: 937-947.
49. Foscarin S, Gianola S, Carulli D, Fazzari P, Mi S, Tamagnone L et al. Overexpression of GAP-43 modifies
the distribution of the receptors for myelin-associated growth-inhibitory proteins in injured Purkinje axons.
Eur J Neurosci 2009; 30: 1837-1848.
50. Redfern RE, Daou MC, Li L, Munson M, Gericke A, Ross AH. A mutant form of PTEN linked to autism.
Protein Sci 2010; 19: 1948-1956.
51. Kwon CH, Luikart BW, Powell CM, Zhou J, Matheny SA, Zhang W et al. Pten regulates neuronal
arborization and social interaction in mice. Neuron 2006; 50: 377-388.
52. Anitha A, Nakamura K, Yamada K, Suda S, Thanseem I, Tsujii M et al. Genetic analyses of roundabout
(ROBO) axon guidance receptors in autism. Am J Med Genet B Neuropsychiatr Genet 2008; 147B: 10191027.
53. Celestino-Soper PB, Shaw CA, Sanders SJ, Li J, Murtha MT, Ercan-Sencicek AG et al. Use of array CGH
to detect exonic copy number variants throughout the genome in autism families detects a novel deletion in
TMLHE. Hum Mol Genet 2011; 20: 4360-4370.
54. Nguyen A, Rauch TA, Pfeifer GP, Hu VW. Global methylation profiling of lymphoblastoid cell lines
reveals epigenetic contributions to autism spectrum disorders and a novel autism candidate gene, RORA,
whose protein product is reduced in autistic brain. FASEB J 2010; 24: 3036-3051.
55. Doulazmi M, Capone F, Frederic F, Bakouche J, Lemaigre-Dubreuil Y, Mariani J. Cerebellar purkinje cell
loss in heterozygous rora+/- mice: a longitudinal study. J Neurogenet 2006; 20: 1-17.
56. Maestrini E, Pagnamenta AT, Lamb JA, Bacchelli E, Sykes NH, Sousa I et al. High-density SNP
association study and copy number variation analysis of the AUTS1 and AUTS5 loci implicate the
IMMP2L-DOCK4 gene region in autism susceptibility. Mol Psychiatry 2010; 15: 954-968.
57. Weiss LA, Escayg A, Kearney JA, Trudeau M, MacDonald BT, Mori M et al. Sodium channels SCN1A,
SCN2A and SCN3A in familial autism. Mol Psychiatry 2003; 8: 186-194.
58. Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ, Willsey AJ et al. De novo mutations
revealed by whole-exome sequencing are strongly associated with autism. Nature 2012; 485: 237-241.
59. Eastwood SL, Law AJ, Everall IP, Harrison PJ. The axonal chemorepellant semaphorin 3A is increased in
the cerebellum in schizophrenia and may contribute to its synaptic pathology. Mol Psychiatry 2003; 8: 148155.
60. Uchida Y, Ohshima T, Yamashita N, Ogawara M, Sasaki Y, Nakamura F et al. Semaphorin3A signaling
mediated by Fyn-dependent tyrosine phosphorylation of collapsin response mediator protein 2 at tyrosine
32. J Biol Chem 2009; 284: 27393-27401.
61. Karlsson RM, Tanaka K, Saksida LM, Bussey TJ, Heilig M, Holmes A.Assessment of glutamate
transporter GLAST (EAAT1)-deficient mice for phenotypes relevant to the negative and
executive/cognitive symptoms of schizophrenia. Neuropsychopharmacology 2009 ; 34: 1578-1589.
62. Munetsuna E, Hattori M, Komatsu S, Sakimoto Y, Ishida A, Sakata S et al. Social isolation stimulates
hippocampal estradiol synthesis. Biochem. Biophys. Res. Commun. 2009; 379: 480-484.
63. Huffman LS, Mitchell MM, O'Connell LA, Hofmann HA. Rising StARs: behavioral, hormonal, and
molecular responses to social challenge and opportunity. Horm Behav 2012; 61: 631-641.
64. Koike H, Ibi D, Mizoguchi H, Nagai T, Nitta A, Takuma K et al. Behavioral abnormality and
pharmacologic response in social isolation-reared mice. Behav Brain Res 2009; 202: 114-121.
65. Nakamura K, Anitha A, Yamada K, Tsujii M, Iwayama Y, Hattori E et al. Genetic and expression analyses
reveal elevated expression of syntaxin 1A ( STX1A) in high functioning autism. Int J
Neuropsychopharmacol 2008; 11: 1073-1084.
66. Nakamura K, Iwata Y, Anitha A, Miyachi T, Toyota T, Yamada S et al. Replication study of Japanese
cohorts supports the role of STX1A in autism susceptibility. Prog Neuropsychopharmacol Biol Psychiatry
2011; 35: 454-458.
67. Jacquemont ML, Sanlaville D, Redon R, Raoul O, Cormier-Daire V, Lyonnet S et al. Array-based
comparative genomic hybridisation identifies high frequency of cryptic chromosomal rearrangements in
patients with syndromic autism spectrum disorders. J Med Genet 2006; 43: 843-849.
68. Van der Aa N, Rooms L, Vandeweyer G, van den Ende J, Reyniers E, Fichera M et al. Fourteen new cases
contribute to the characterization of the 7q11.23 microduplication syndrome. Eur J Med Genet 2009; 52:
94-100.
69. Marui T, Funatogawa I, Koishi S, Yamamoto K, Matsumoto H, Hashimoto O et al. Association between
autism and variants in the wingless-type MMTV integration site family member 2 (WNT2) gene. Int J
Neuropsychopharmacol 2010; 13: 443-449.