1932

Abstract

The etiology of autism spectrum disorder (ASD) is complex, involving both genetic and environmental contributions to individual and population-level liability. Early researchers hypothesized that ASD arises from polygenic inheritance, but later results, such as the identification of mutations in certain genes that are responsible for syndromes associated with ASD, led others to propose that de novo mutations of major effect would account for most cases. This yin and yang of monogenic causes and polygenic inheritance continues to this day. The development of genome-wide genotyping and sequencing techniques has resulted in remarkable advances in our understanding of the genetic architecture of risk for ASD. The combined research findings provide solid evidence that ASD is a complex polygenic disorder. Rare de novo and inherited variations act within the context of a common-variant genetic load, and this load accounts for the largest portion of ASD liability.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-genom-083115-022647
2017-08-31
2024-06-16
Loading full text...

Full text loading...

/deliver/fulltext/genom/18/1/annurev-genom-083115-022647.html?itemId=/content/journals/10.1146/annurev-genom-083115-022647&mimeType=html&fmt=ahah

Literature Cited

  1. Abrahams BS, Geschwind DH. 1.  2008. Advances in autism genetics: on the threshold of a new neurobiology. Nat. Rev. Genet. 9:341–55 [Google Scholar]
  2. Adolphs R. 2.  2001. The neurobiology of social cognition. Curr. Opin. Neurobiol. 11:231–39 [Google Scholar]
  3. 3. Am. Psychiatr. Assoc. 2000. Diagnostic and Statistical Manual of Mental Disorders: DSM-IV-TR Arlington, Tex.: Am. Psychiatr. Publ. [Google Scholar]
  4. 4. Am. Psychiatr. Assoc. 2013. Diagnostic and Statistical Manual of Mental Disorders: DSM-5 Washington, DC: Am. Psychiatr. Assoc. Publ. [Google Scholar]
  5. Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY. 5.  1999. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat. Genet. 23:185–88 [Google Scholar]
  6. Amodio DM, Frith CD. 6.  2006. Meeting of minds: the medial frontal cortex and social cognition. Nat. Rev. Neurosci. 7:268–77 [Google Scholar]
  7. Anney R, Klei L, Pinto D, Almeida J, Bacchelli E. 7.  et al. 2012. Individual common variants exert weak effects on the risk for autism spectrum disorders. Hum. Mol. Genet. 21:4781–92 [Google Scholar]
  8. Ariani F, Hayek G, Rondinella D, Artuso R, Mencarelli MA. 8.  et al. 2008. FOXG1 is responsible for the congenital variant of Rett syndrome. Am. J. Hum. Genet. 83:89–93 [Google Scholar]
  9. 9. Autism Dev. Disabil. Monit. Netw. Surveill. Year 2010. Princ. Investig. 2014. Prevalence of autism spectrum disorder among children aged 8 years—autism and developmental disabilities monitoring network, 11 sites, United States, 2010. Morb. Mortal. Wkly. Rep. Surveill. Summ. 63:SS021–21 [Google Scholar]
  10. Bailey A, Le Couteur A, Gottesman I, Bolton P, Simonoff E. 10.  et al. 1995. Autism as a strongly genetic disorder: evidence from a British twin study. Psychol. Med. 25:63–77 [Google Scholar]
  11. Baird G, Simonoff E, Pickles A, Chandler S, Loucas T. 11.  et al. 2006. Prevalence of disorders of the autism spectrum in a population cohort of children in South Thames: the Special Needs and Autism Project (SNAP). Lancet 368:210–15 [Google Scholar]
  12. Bernhardt BC, Valk SL, Silani G, Bird G, Frith U, Singer T. 12.  2014. Selective disruption of sociocognitive structural brain networks in autism and alexithymia. Cereb. Cortex 24:3258–67 [Google Scholar]
  13. Bernier R, Golzio C, Xiong B, Stessman HA, Coe BP. 13.  et al. 2014. Disruptive CHD8 mutations define a subtype of autism early in development. Cell 158:263–76 [Google Scholar]
  14. Blumenthal I, Ragavendran A, Erdin S, Klei L, Sugathan A. 14.  et al. 2014. Transcriptional consequences of 16p11.2 deletion and duplication in mouse cortex and multiplex autism families. Am. J. Hum. Genet. 94:870–83 [Google Scholar]
  15. Brand H, Collins RL, Hanscom C, Rosenfeld JA, Pillalamarri V. 15.  et al. 2015. Paired-duplication signatures mark cryptic inversions and other complex structural variation. Am. J. Hum. Genet. 97:170–76 [Google Scholar]
  16. Brand H, Pillalamarri V, Collins RL, Eggert S, O'Dushlaine C. 16.  et al. 2014. Cryptic and complex chromosomal aberrations in early-onset neuropsychiatric disorders. Am. J. Hum. Genet. 95:454–61 [Google Scholar]
  17. Brown WT, Friedman E, Jenkins EC, Brooks J, Wisniewski K. 17.  et al. 1982. Association of fragile X syndrome with autism. Lancet 319:100 [Google Scholar]
  18. Buckner RL, Andrews-Hanna JR, Schacter DL. 18.  2008. The brain's default network: anatomy, function, and relevance to disease. Ann. N.Y. Acad. Sci. 1124:1–38 [Google Scholar]
  19. Bulik-Sullivan BK, Finucane HK, Anttila V, Gusev A, Day FR. 19.  et al. 2015. An atlas of genetic correlations across human diseases and traits. Nat. Genet. 47:1236–41 [Google Scholar]
  20. Bulik-Sullivan BK, Loh P-R, Finucane HK, Ripke S, Yang J. 20.  et al. 2015. LD score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat. Genet. 47:291–95 [Google Scholar]
  21. Buxbaum JD, Daly MJ, Devlin B, Lehner T, Roeder K. 21.  et al. 2012. The Autism Sequencing Consortium: large-scale, high-throughput sequencing in autism spectrum disorders. Neuron 76:1052–56 [Google Scholar]
  22. Buxbaum JD, Silverman J, Keddache M, Smith CJ, Hollander E. 22.  et al. 2004. Linkage analysis for autism in a subset families with obsessive-compulsive behaviors: evidence for an autism susceptibility gene on chromosome 1 and further support for susceptibility genes on chromosome 6 and 19. Mol. Psychiatry 9:144–50 [Google Scholar]
  23. Buxbaum JD, Silverman JM, Smith CJ, Kilifarski M, Reichert J. 23.  et al. 2001. Evidence for a susceptibility gene for autism on chromosome 2 and for genetic heterogeneity. Am. J. Hum. Genet. 68:1514–20 [Google Scholar]
  24. Ceballos-Chávez M, Subtil-Rodríguez A, Giannopoulou EG, Soronellas D, Vázquez-Chávez E. 24.  et al. 2015. The chromatin remodeler CHD8 is required for activation of progesterone receptor-dependent enhancers. PLOS Genet 11:e1005174 [Google Scholar]
  25. Cederlund M, Hagberg B, Billstedt E, Gillberg IC, Gillberg C. 25.  2008. Asperger syndrome and autism: a comparative longitudinal follow-up study more than 5 years after original diagnosis. J. Autism Dev. Disord. 38:72–85 [Google Scholar]
  26. Chahrour M, Zoghbi HY. 26.  2007. The story of Rett syndrome: from clinic to neurobiology. Neuron 56:422–37 [Google Scholar]
  27. Chaste P, Klei L, Sanders SJ, Hus V, Murtha MT. 27.  et al. 2015. A genome-wide association study of autism using the Simons Simplex Collection: Does reducing phenotypic heterogeneity in autism increase genetic homogeneity?. Biol. Psychiatry 77:775–84 [Google Scholar]
  28. Chaste P, Klei L, Sanders SJ, Murtha MT, Hus V. 28.  et al. 2013. Adjusting head circumference for covariates in autism: clinical correlates of a highly heritable continuous trait. Biol. Psychiatry 74:576–84 [Google Scholar]
  29. Chaste P, Sanders SJ, Mohan KN, Klei L, Song Y. 29.  et al. 2014. Modest impact on risk for autism spectrum disorder of rare copy number variants at 15q11.2, specifically breakpoints 1 to 2. Autism Res 7:355–62 [Google Scholar]
  30. Choi GB, Yim YS, Wong H, Kim S, Kim H. 30.  et al. 2016. The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring. Science 351:933–39 [Google Scholar]
  31. Clarke T-K, Lupton MK, Fernandez-Pujals AM, Starr J, Davies G. 31.  et al. 2016. Common polygenic risk for autism spectrum disorder (ASD) is associated with cognitive ability in the general population. Mol. Psychiatry 21:419–25 [Google Scholar]
  32. Constantino JN. 32.  2011. The quantitative nature of autistic social impairment. Pediatr. Res. 69:55R–62R [Google Scholar]
  33. Constantino JN, Todd RD. 33.  2000. Genetic structure of reciprocal social behavior. Am. J. Psychiatry 157:2043–45 [Google Scholar]
  34. Constantino JN, Todd RD. 34.  2003. Autistic traits in the general population: a twin study. Arch. Gen. Psychiatry 60:524–30 [Google Scholar]
  35. Constantino JN, Zhang Y, Frazier T, Abbacchi AM, Law P. 35.  2010. Sibling recurrence and the genetic epidemiology of autism. Am. J. Psychiatry 167:1349–56 [Google Scholar]
  36. Cotney J, Muhle RA, Sanders SJ, Liu L, Willsey AJ. 36.  et al. 2015. The autism-associated chromatin modifier CHD8 regulates other autism risk genes during human neurodevelopment. Nat. Commun. 6:6404 [Google Scholar]
  37. 37. Cross-Disord. Group Psychiatr. Genom. Consort. 2013. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nat. Genet. 45:984–94 [Google Scholar]
  38. 38. Cross-Disord. Group Psychiatr. Genom. Consort. 2013. Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet 381:1371–79 [Google Scholar]
  39. D'Angelo D, Lebon S, Chen Q, Martin-Brevet S, Green Snyder L. 39.  et al. 2016. Defining the effect of the 16p11.2 duplication on cognition, behavior, and medical comorbidities. JAMA Psychiatry 73:20–30 [Google Scholar]
  40. de los Campos G, Vazquez AI, Fernando R, Klimentidis YC, Sorensen D. 40.  2013. Prediction of complex human traits using the genomic best linear unbiased predictor. PLOS Genet 9:e1003608 [Google Scholar]
  41. De Rubeis S, He X, Goldberg AP, Poultney CS, Samocha K. 41.  et al. 2014. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature 515:209–15 [Google Scholar]
  42. Devlin B, Melhem N, Roeder K. 42.  2011. Do common variants play a role in risk for autism? Evidence and theoretical musings. Brain Res 1380:78–84 [Google Scholar]
  43. Dong S, Walker MF, Carriero NJ, DiCola M, Willsey AJ. 43.  et al. 2014. De novo insertions and deletions of predominantly paternal origin are associated with autism spectrum disorder. Cell Rep 9:16–23 [Google Scholar]
  44. Durand CM, Betancur C, Boeckers TM, Bockmann J, Chaste P. 44.  et al. 2007. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat. Genet. 39:25–27 [Google Scholar]
  45. Fischbach GD, Lord C. 45.  2010. The Simons Simplex Collection: a resource for identification of autism genetic risk factors. Neuron 68:192–95 [Google Scholar]
  46. Fisher R. 46.  1918. The correlation between relatives on the supposition of Mendelian inheritance. Philos. Trans. R. Soc. Edinb. 52:399–433 [Google Scholar]
  47. Frith U. 47.  1989. L'énigme de l'autisme Paris: Odile Jacob, 2nd ed.. [Google Scholar]
  48. Fromer M, Roussos P, Sieberts SK, Johnson JS, Kavanagh DH. 48.  et al. 2016. Gene expression elucidates functional impact of polygenic risk for schizophrenia. Nat. Neurosci. 19:1442–53 [Google Scholar]
  49. Gaugler T, Klei L, Sanders SJ, Bodea CA, Goldberg AP. 49.  et al. 2014. Most genetic risk for autism resides with common variation. Nat. Genet. 46:881–85 [Google Scholar]
  50. Georgiades S, Szatmari P, Boyle M, Hanna S, Duku E. 50.  et al. 2013. Investigating phenotypic heterogeneity in children with autism spectrum disorder: a factor mixture modeling approach. J. Child Psychol. Psychiatry 54:206–15 [Google Scholar]
  51. Glessner JT, Wang K, Cai G, Korvatska O, Kim CE. 51.  et al. 2009. Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature 459:569–73 [Google Scholar]
  52. Golzio C, Willer J, Talkowski ME, Oh EC, Taniguchi Y. 52.  et al. 2012. KCTD13 is a major driver of mirrored neuroanatomical phenotypes of the 16p11.2 copy number variant. Nature 485:363–67 [Google Scholar]
  53. Gratten J, Wray NR, Peyrot WJ, McGrath JJ, Visscher PM, Goddard ME. 53.  2016. Risk of psychiatric illness from advanced paternal age is not predominantly from de novo mutations. Nat. Genet. 48:718–24 [Google Scholar]
  54. Green Snyder L, D'Angelo D, Chen Q, Bernier R, Goin-Kochel RP. 54.  et al. 2016. Autism spectrum disorder, developmental and psychiatric features in 16p11.2 duplication. J. Autism Dev. Disord. 46:2734–48 [Google Scholar]
  55. Grønborg TK, Schendel DE, Parner ET. 55.  2013. Recurrence of autism spectrum disorders in full- and half-siblings and trends over time: a population-based cohort study. JAMA Pediatr 167:947–53 [Google Scholar]
  56. Guilmatre A, Dubourg C, Mosca A-L, Legallic S, Goldenberg A. 56.  et al. 2009. Recurrent rearrangements in synaptic and neurodevelopmental genes and shared biologic pathways in schizophrenia, autism, and mental retardation. Arch. Gen. Psychiatry 66:947–56 [Google Scholar]
  57. Halladay AK, Bishop S, Constantino JN, Daniels AM, Koenig K. 57.  et al. 2015. Sex and gender differences in autism spectrum disorder: summarizing evidence gaps and identifying emerging areas of priority. Mol. Autism 6:36 [Google Scholar]
  58. Hastings P, Lupski JR, Rosenberg SM, Ira G. 58.  2009. Mechanisms of change in gene copy number. Nat. Rev. Genet. 10:551–64 [Google Scholar]
  59. He X, Sanders SJ, Liu L, De Rubeis S, Lim ET. 59.  et al. 2013. Integrated model of de novo and inherited genetic variants yields greater power to identify risk genes. PLOS Genet 9:e1003671 [Google Scholar]
  60. Hernandez LM, Rudie JD, Green SA, Bookheimer S, Dapretto M. 60.  2015. Neural signatures of autism spectrum disorders: insights into brain network dynamics. Neuropsychopharmacology 40:171–89 [Google Scholar]
  61. 61. Hill WD, Davies G, CHARGE Cogn. Work. Group, Liewald DC, McIntosh AM, Deary IJ. 2016. Age-dependent pleiotropy between general cognitive function and major psychiatric disorders. Biol. Psychiatry 80:266–73 [Google Scholar]
  62. Hodge JC, Mitchell E, Pillalamarri V, Toler TL, Bartel F. 62.  et al. 2014. Disruption of MBD5 contributes to a spectrum of psychopathology and neurodevelopmental abnormalities. Mol. Psychiatry 19:368–79 [Google Scholar]
  63. Huerta M, Bishop SL, Duncan A, Hus V, Lord C. 63.  2012. Application of DSM-5 criteria for autism spectrum disorder to three samples of children with DSM-IV diagnoses of pervasive developmental disorders. Am. J. Psychiatry 169:1056–64 [Google Scholar]
  64. Hultman CM, Sandin S, Levine SZ, Lichtenstein P, Reichenberg A. 64.  2011. Advancing paternal age and risk of autism: new evidence from a population-based study and a meta-analysis of epidemiological studies. Mol. Psychiatry 16:1203–12 [Google Scholar]
  65. Hus V, Pickles A, Cook EH, Risi S, Lord C. 65.  2007. Using the autism diagnostic interview—revised to increase phenotypic homogeneity in genetic studies of autism. Biol. Psychiatry 61:438–48 [Google Scholar]
  66. 66. Int. Schizophr. Consort. 2009. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460:748–52 [Google Scholar]
  67. Iossifov I, Levy D, Allen J, Ye K, Ronemus M. 67.  et al. 2015. Low load for disruptive mutations in autism genes and their biased transmission. PNAS 112:E5600–7 [Google Scholar]
  68. Iossifov I, O'Roak BJ, Sanders SJ, Ronemus M, Krumm N. 68.  et al. 2014. The contribution of de novo coding mutations to autism spectrum disorder. Nature 515:216–21 [Google Scholar]
  69. Iossifov I, Ronemus M, Levy D, Wang Z, Hakker I. 69.  et al. 2012. De novo gene disruptions in children on the autistic spectrum. Neuron 74:285–99 [Google Scholar]
  70. Jacquemont S, Reymond A, Zufferey F, Harewood L, Walters RG. 70.  et al. 2011. Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus. Nature 478:97–102 [Google Scholar]
  71. Jamain S, Quach H, Betancur C, Råstam M, Colineaux C. 71.  et al. 2003. Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat. Genet. 34:27–29 [Google Scholar]
  72. Jorde LB, Hasstedt SJ, Ritvo ER, Mason-Brothers A, Freeman BJ. 72.  et al. 1991. Complex segregation analysis of autism. Am. J. Hum. Genet. 49:932–38 [Google Scholar]
  73. Just MA, Cherkassky VL, Keller TA, Kana RK, Minshew NJ. 73.  2007. Functional and anatomical cortical underconnectivity in autism: evidence from an fMRI study of an executive function task and corpus callosum morphometry. Cereb. Cortex 17:951–61 [Google Scholar]
  74. Kaiser MD, Hudac CM, Shultz S, Lee SM, Cheung C. 74.  et al. 2010. Neural signatures of autism. PNAS 107:21223–28 [Google Scholar]
  75. Kanner L. 75.  1943. Autistic disturbances of affective contact. Nerv. Child 1943:217–50 [Google Scholar]
  76. Kendler KS, Ohlsson H, Mezuk B, Sundquist JO, Sundquist K. 76.  2016. Observed cognitive performance and deviation from familial cognitive aptitude at age 16 years and ages 18 to 20 years and risk for schizophrenia and bipolar illness in a Swedish national sample. JAMA Psychiatry 73:465–71 [Google Scholar]
  77. Kendler KS, Ohlsson H, Sundquist J, Sundquist K. 77.  2015. IQ and schizophrenia in a Swedish national sample: their causal relationship and the interaction of IQ with genetic risk. Am. J. Psychiatry 172:259–65 [Google Scholar]
  78. Kennedy DP, Courchesne E. 78.  2008. Functional abnormalities of the default network during self- and other-reflection in autism. Soc. Cogn. Affect. Neurosci. 3:177–90 [Google Scholar]
  79. Klei L, Sanders SJ, Murtha MT, Hus V, Lowe JK. 79.  et al. 2012. Common genetic variants, acting additively, are a major source of risk for autism. Mol. Autism 3:9 [Google Scholar]
  80. Kong A, Frigge ML, Masson G, Besenbacher S, Sulem P. 80.  et al. 2012. Rate of de novo mutations and the importance of father's age to disease risk. Nature 488:471–75 [Google Scholar]
  81. Kosmicki JA, Samocha KE, Howrigan DP, Sanders SJ, Slowikowski K. 81.  et al. 2017. Refining the role of de novo protein-truncating variants in neurodevelopmental disorders by using population reference samples. Nat. Genet. 49:504–10 [Google Scholar]
  82. Krumm N, O'Roak BJ, Karakoc E, Mohajeri K, Nelson B. 82.  et al. 2013. Transmission disequilibrium of small CNVs in simplex autism. Am. J. Hum. Genet. 93:595–606 [Google Scholar]
  83. Kumar RA, KaraMohamed S, Sudi J, Conrad DF, Brune C. 83.  et al. 2008. Recurrent 16p11.2 microdeletions in autism. Hum. Mol. Genet. 17:628–38 [Google Scholar]
  84. Leblond CS, Nava C, Polge A, Gauthier J, Huguet G. 84.  et al. 2014. Meta-analysis of shank mutations in autism spectrum disorders: a gradient of severity in cognitive impairments. PLOS Genet 10:e1004580 [Google Scholar]
  85. Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E. 85.  et al. 2016. Analysis of protein-coding genetic variation in 60,706 humans. Nature 536:285–91 [Google Scholar]
  86. Lencz T, Knowles E, Davies G, Guha S, Liewald DC. 86.  et al. 2014. Molecular genetic evidence for overlap between general cognitive ability and risk for schizophrenia: a report from the Cognitive Genomics consorTium (COGENT). Mol. Psychiatry 19:168–74 [Google Scholar]
  87. Leppa VM, Kravitz SN, Martin CL, Andrieux J, Le Caignec C. 87.  et al. 2016. Rare inherited and de novo CNVs reveal complex contributions to ASD risk in multiplex families. Am. J. Hum. Genet. 99:540–54 [Google Scholar]
  88. Lichtenstein P, Carlström E, Råstam M, Gillberg C, Anckarsäter H. 88.  2010. The genetics of autism spectrum disorders and related neuropsychiatric disorders in childhood. Am. J. Psychiatry 167:1357–63 [Google Scholar]
  89. Liss M, Harel B, Fein D, Allen D, Dunn M. 89.  et al. 2001. Predictors and correlates of adaptive functioning in children with developmental disorders. J. Autism Dev. Disord. 31:219–30 [Google Scholar]
  90. Liu X-Q, Paterson AD, Szatmari P. 90.  Autism Genome Proj. Consort 2008. Genome-wide linkage analyses of quantitative and categorical autism subphenotypes. Biol. Psychiatry 64:561–70 [Google Scholar]
  91. Lord C, Risi S, Lambrecht L, Cook EH, Leventhal BL. 91.  et al. 2000. The autism diagnostic observation schedule-generic: a standard measure of social and communication deficits associated with the spectrum of autism. J. Autism Dev. Disord. 30:205–23 [Google Scholar]
  92. Loviglio MN, Leleu M, Männik K, Passeggeri M, Giannuzzi G. 92.  et al. 2017. Chromosomal contacts connect loci associated with autism, BMI and head circumference phenotypes. Mol. Psychiatry 22:836–49 [Google Scholar]
  93. Lundström S, Chang Z, Råstam M, Gillberg C, Larsson H. 93.  et al. 2012. Autism spectrum disorders and autistic like traits: similar etiology in the extreme end and the normal variation. Arch. Gen. Psychiatry 69:46–52 [Google Scholar]
  94. MacArthur JAL, Spector TD, Lindsay SJ, Mangino M, Gill R. 94.  et al. 2014. The rate of nonallelic homologous recombination in males is highly variable, correlated between monozygotic twins and independent of age. PLOS Genet 10:e1004195 [Google Scholar]
  95. Marshall CR, Noor A, Vincent JB, Lionel AC, Feuk L. 95.  et al. 2008. Structural variation of chromosomes in autism spectrum disorder. Am. J. Hum. Genet. 82:477–88 [Google Scholar]
  96. McCarthy SE, Gillis J, Kramer M, Lihm J, Yoon S. 96.  et al. 2014. De novo mutations in schizophrenia implicate chromatin remodeling and support a genetic overlap with autism and intellectual disability. Mol. Psychiatry 19:652–58 [Google Scholar]
  97. McCarthy SE, Makarov V, Kirov G, Addington AM, McClellan J. 97.  et al. 2009. Microduplications of 16p11.2 are associated with schizophrenia. Nat. Genet. 41:1223–27 [Google Scholar]
  98. McIntosh AM, Gow A, Luciano M, Davies G, Liewald DC. 98.  et al. 2013. Polygenic risk for schizophrenia is associated with cognitive change between childhood and old age. Biol. Psychiatry 73:938–43 [Google Scholar]
  99. Moreno-De-Luca A, Evans DW, Boomer KB, Hanson E, Bernier R. 99.  et al. 2015. The role of parental cognitive, behavioral, and motor profiles in clinical variability in individuals with chromosome 16p11.2 deletions. JAMA Psychiatry 72:119–26 [Google Scholar]
  100. Moreno-De-Luca D, Moreno-De-Luca A, Cubells JF, Sanders SJ. 100.  2014. Cross-disorder comparison of four neuropsychiatric CNV loci. Curr. Genet. Med. Rep 2151–61 [Google Scholar]
  101. Neale BM, Kou Y, Liu L, Ma'ayan A, Samocha KE. 101.  et al. 2012. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 485:242–45 [Google Scholar]
  102. Notwell JH, Heavner WE, Darbandi SF, Katzman S, McKenna WL. 102.  et al. 2016. TBR1 regulates autism risk genes in the developing neocortex. Genome Res 26:1013–22 [Google Scholar]
  103. O'Roak BJ, Vives L, Girirajan S, Karakoc E, Krumm N. 103.  et al. 2012. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485:246–50 [Google Scholar]
  104. Ozonoff S, Young GS, Carter A, Messinger D, Yirmiya N. 104.  et al. 2011. Recurrence risk for autism spectrum disorders: a Baby Siblings Research Consortium study. Pediatrics 128:e488–95 [Google Scholar]
  105. Parikshak NN, Luo R, Zhang A, Won H, Lowe JK. 105.  et al. 2013. Integrative functional genomic analyses implicate specific molecular pathways and circuits in autism. Cell 155:1008–21 [Google Scholar]
  106. Pickles A, Bolton P, Macdonald H, Bailey A, Le Couteur A. 106.  et al. 1995. Latent-class analysis of recurrence risks for complex phenotypes with selection and measurement error: a twin and family history study of autism. Am. J. Hum. Genet. 57:717–26 [Google Scholar]
  107. Pinto D, Pagnamenta AT, Klei L, Anney R, Merico D. 107.  et al. 2010. Functional impact of global rare copy number variation in autism spectrum disorders. Nature 466:368–72 [Google Scholar]
  108. Poultney CS, Goldberg AP, Drapeau E, Kou Y, Harony-Nicolas H. 108.  et al. 2013. Identification of small exonic CNV from whole-exome sequence data and application to autism spectrum disorder. Am. J. Hum. Genet. 93:607–19 [Google Scholar]
  109. Power RA, Kyaga S, Uher R, MacCabe JH, Långström N. 109.  et al. 2013. Fecundity of patients with schizophrenia, autism, bipolar disorder, depression, anorexia nervosa, or substance abuse versus their unaffected siblings. JAMA Psychiatry 70:22–30 [Google Scholar]
  110. Risch N, Hoffmann TJ, Anderson M, Croen LA, Grether JK, Windham GC. 110.  2014. Familial recurrence of autism spectrum disorder: evaluating genetic and environmental contributions. Am. J. Psychiatry 171:1206–13 [Google Scholar]
  111. Robinson EB, Koenen KC, McCormick MC, Munir K, Hallett V. 111.  et al. 2011. Evidence that autistic traits show the same etiology in the general population and at the quantitative extremes (5%, 2.5%, and 1%). Arch. Gen. Psychiatry 68:1113–21 [Google Scholar]
  112. Robinson EB, Samocha KE, Kosmicki JA, McGrath L, Neale BM. 112.  et al. 2014. Autism spectrum disorder severity reflects the average contribution of de novo and familial influences. PNAS 111:15161–65 [Google Scholar]
  113. Robinson EB, St. Pourcain B, Anttila V, Kosmicki JA, Bulik-Sullivan B. 113.  et al. 2016. Genetic risk for autism spectrum disorders and neuropsychiatric variation in the general population. Nat. Genet. 48:552–55 [Google Scholar]
  114. Ronald A, Happé F, Bolton P, Butcher LM, Price TS. 114.  et al. 2006. Genetic heterogeneity between the three components of the autism spectrum: a twin study. J. Am. Acad. Child Adolesc. Psychiatry 45:691–99 [Google Scholar]
  115. Ronald A, Happé F, Price TS, Baron-Cohen S, Plomin R. 115.  2006. Phenotypic and genetic overlap between autistic traits at the extremes of the general population. J. Am. Acad. Child Adolesc. Psychiatry 45:1206–14 [Google Scholar]
  116. Ronemus M, Iossifov I, Levy D, Wigler M. 116.  2014. The role of de novo mutations in the genetics of autism spectrum disorders. Nat. Rev. Genet. 15:133–41 [Google Scholar]
  117. Rutter M. 117.  1978. Diagnosis and definition of childhood autism. J. Autism Child. Schizophr. 8:139–61 [Google Scholar]
  118. Samocha KE, Robinson EB, Sanders SJ, Stevens C, Sabo A. 118.  et al. 2014. A framework for the interpretation of de novo mutation in human disease. Nat. Genet. 46:944–50 [Google Scholar]
  119. Sanders SJ, Ercan-Sencicek AG, Hus V, Luo R, Murtha MT. 119.  et al. 2011. Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron 70:863–85 [Google Scholar]
  120. Sanders SJ, He X, Willsey AJ, Ercan-Sencicek AG, Samocha KE. 120.  et al. 2015. Insights into autism spectrum disorder genomic architecture and biology from 71 risk loci. Neuron 87:1215–33 [Google Scholar]
  121. Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ. 121.  et al. 2012. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 485:237–41 [Google Scholar]
  122. Sandin S, Lichtenstein P, Kuja-Halkola R, Larsson H, Hultman CM, Reichenberg A. 122.  2014. The familial risk of autism. JAMA 311:1770–77 [Google Scholar]
  123. Sebat J, Lakshmi B, Malhotra D, Troge J, Lese-Martin C. 123.  et al. 2007. Strong association of de novo copy number mutations with autism. Science 316:445–49 [Google Scholar]
  124. Skuse DH. 124.  2007. Rethinking the nature of genetic vulnerability to autistic spectrum disorders. Trends Genet 23:387–95 [Google Scholar]
  125. St. Pourcain B, Wang K, Glessner JT, Golding J, Steer C. 125.  et al. 2010. Association between a high-risk autism locus on 5p14 and social communication spectrum phenotypes in the general population. Am. J. Psychiatry 167:1364–72 [Google Scholar]
  126. Stefansson H, Meyer-Lindenberg A, Steinberg S, Magnusdottir B, Morgen K. 126.  et al. 2014. CNVs conferring risk of autism or schizophrenia affect cognition in controls. Nature 505:361–66 [Google Scholar]
  127. Steffenburg S, Gillberg C, Hellgren L, Andersson L, Gillberg IC. 127.  et al. 1989. A twin study of autism in Denmark, Finland, Iceland, Norway and Sweden. J. Child Psychol. Psychiatry 30:405–16 [Google Scholar]
  128. Stessman HA, Xiong B, Coe BP, Wang T, Hoekzema K. 128.  et al. 2017. Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Nat. Genet. 49:515–26 [Google Scholar]
  129. Stoner R, Chow ML, Boyle MP, Sunkin SM, Mouton PR. 129.  et al. 2014. Patches of disorganization in the neocortex of children with autism. N. Engl. J. Med. 370:1209–19 [Google Scholar]
  130. Sugathan A, Biagioli M, Golzio C, Erdin S, Blumenthal I. 130.  et al. 2014. CHD8 regulates neurodevelopmental pathways associated with autism spectrum disorder in neural progenitors. PNAS 111:E4468–77 [Google Scholar]
  131. Sullivan PF, Magnusson C, Reichenberg A, Boman M, Dalman C. 131.  et al. 2012. Family history of schizophrenia and bipolar disorder as risk factors for autism. Arch. Gen. Psychiatry 69:1099–103 [Google Scholar]
  132. Szatmari P, Paterson A, Zwaigenbaum L, Roberts W, Brian J. 132.  et al. 2007. Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat. Genet. 39:319–28 [Google Scholar]
  133. Takata A, Ionita-Laza I, Gogos JA, Xu B, Karayiorgou M. 133.  2016. De novo synonymous mutations in regulatory elements contribute to the genetic etiology of autism and schizophrenia. Neuron 89:940–47 [Google Scholar]
  134. Talkowski ME, Rosenfeld JA, Blumenthal I, Pillalamarri V, Chiang C. 134.  et al. 2012. Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries. Cell 149:525–37 [Google Scholar]
  135. Tamir DI, Thornton MA, Contreras JM, Mitchell JP. 135.  2016. Neural evidence that three dimensions organize mental state representation: rationality, social impact, and valence. PNAS 113:194–99 [Google Scholar]
  136. Tick B, Colvert E, McEwen F, Stewart C, Woodhouse E. 136.  et al. 2016. Autism spectrum disorders and other mental health problems: exploring etiological overlaps and phenotypic causal associations. J. Am. Acad. Child Adolesc. Psychiatry 55:106–113.e4 [Google Scholar]
  137. Turner TN, Hormozdiari F, Duyzend MH, McClymont SA, Hook PW. 137.  et al. 2016. Genome sequencing of autism-affected families reveals disruption of putative noncoding regulatory DNA. Am. J. Hum. Genet. 98:58–74 [Google Scholar]
  138. Turner TN, Sharma K, Oh EC, Liu YP, Collins RL. 138.  et al. 2015. Loss of δ-catenin function in severe autism. Nature 520:51–56 [Google Scholar]
  139. Vilhjálmsson BJ, Yang J, Finucane HK, Gusev A, Lindström S. 139.  et al. 2015. Modeling linkage disequilibrium increases accuracy of polygenic risk scores. Am. J. Hum. Genet. 97:576–92 [Google Scholar]
  140. Virkud YV, Todd RD, Abbacchi AM, Zhang Y, Constantino JN. 140.  2009. Familial aggregation of quantitative autistic traits in multiplex versus simplex autism. Am. J. Med. Genet. B 150B328–34 [Google Scholar]
  141. Walters RG, Jacquemont S, Valsesia A, de Smith AJ, Martinet D. 141.  et al. 2010. A new highly penetrant form of obesity due to deletions on chromosome 16p11.2. Nature 463:671–75 [Google Scholar]
  142. Wang K, Zhang H, Ma D, Bucan M, Glessner JT. 142.  et al. 2009. Common genetic variants on 5p14.1 associate with autism spectrum disorders. Nature 459:528–33 [Google Scholar]
  143. Weiner DJ, Wigdor EM, Ripke S, Walters RK, Kosmicki JA. 143.  et al. 2017. Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders.. Nat. Genet. 49978–85 [Google Scholar]
  144. Weiss LA, Arking DE. 144.  Gene Discov. Proj. Johns Hopkins Autism Consort 2009. A genome-wide linkage and association scan reveals novel loci for autism. Nature 461:802–8 [Google Scholar]
  145. Weiss LA, Shen Y, Korn JM, Arking DE, Miller DT. 145.  et al. 2008. Association between microdeletion and microduplication at 16p11.2 and autism. N. Engl. J. Med. 358:667–75 [Google Scholar]
  146. Williams DL, Goldstein G, Minshew NJ. 146.  2006. Neuropsychologic functioning in children with autism: further evidence for disordered complex information-processing. Child Neuropsychol 12:279–98 [Google Scholar]
  147. Willsey AJ, Sanders SJ, Li M, Dong S, Tebbenkamp AT. 147.  et al. 2013. Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism. Cell 155:997–1007 [Google Scholar]
  148. Wing L, Gould J. 148.  1979. Severe impairments of social interaction and associated abnormalities in children: epidemiology and classification. J. Autism Dev. Disord. 9:11–29 [Google Scholar]
  149. Yang J, Benyamin B, McEvoy BP, Gordon S, Henders AK. 149.  et al. 2010. Common SNPs explain a large proportion of heritability for human height. Nat. Genet. 42:565–69 [Google Scholar]
  150. Yang J, Lee SH, Goddard ME, Visscher PM. 150.  2011. GCTA: a tool for genome-wide complex trait analysis. Am. J. Hum. Genet. 88:76–82 [Google Scholar]
/content/journals/10.1146/annurev-genom-083115-022647
Loading
/content/journals/10.1146/annurev-genom-083115-022647
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error