1932

Abstract

Next-generation sequencing, which allows genome-wide detection of rare and de novo mutations, is transforming neuropsychiatric disease genetics through identifying on an unprecedented scale genes and protein-coding mutations that confer risk. Although understanding how regulatory variants influence risk remains a challenge, we are likely transitioning into a phase of neuropsychiatric disease genetics in which the rate-limiting step may no longer be gene discovery. Instead, the future will concentrate more on the biological and clinical translation of the torrent of specific risk mutations identified through next-generation sequencing. Here, we review the recent progress that resulted specifically from exome sequencing and emphasize the need for rigorous statistical evaluation of the expanding data sets, as well as expanded functional analysis of implicated proteins and mutations. Then, we introduce some of the expected opportunities and challenges investigators face when moving beyond the exome. Finally, we briefly highlight the challenge of deriving translational benefit from the progress in genetics.

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2015-07-08
2024-03-29
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Literature Cited

  1. 1000 Genomes Proj. Consort., Abecasis GR, Auton A, Brooks LD, DePristo MA et al. 2012. An integrated map of genetic variation from 1,092 human genomes. Nature 491:56–65 [Google Scholar]
  2. Bahassi EM, Stambrook PJ. 2014. Next-generation sequencing technologies: breaking the sound barrier of human genetics. Mutagenesis 29:303–10 [Google Scholar]
  3. Barcia G, Fleming MR, Deligniere A, Gazula VR, Brown MR. et al. 2012. De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy. Nat. Genet. 44:1255–59 [Google Scholar]
  4. Bateup HS, Johnson CA, Denefrio CL, Saulnier JL, Kornacker K, Sabatini BL. 2013. Excitatory/inhibitory synaptic imbalance leads to hippocampal hyperexcitability in mouse models of tuberous sclerosis. Neuron 78:510–22 [Google Scholar]
  5. Bearden D, Strong A, Ehnot J, DiGiovine M, Dlugos D, Goldberg EM. 2014. Targeted treatment of migrating partial seizures of infancy with quinidine. Ann. Neurol. 76:457–61 [Google Scholar]
  6. Bell CJ, Dinwiddie DL, Miller NA, Hateley SL, Ganusova EE. et al. 2011. Carrier testing for severe childhood recessive diseases by next-generation sequencing. Sci. Transl. Med. 3:65ra4 [Google Scholar]
  7. Ben-Shachar S, Lanpher B, German JR, Qasaymeh M, Potocki L. et al. 2009. Microdeletion 15q13.3: a locus with incomplete penetrance for autism, mental retardation, and psychiatric disorders. J. Med. Genet. 46:382–88 [Google Scholar]
  8. Bernier R, Golzio C, Xiong B, Stessman HA, Coe BP. et al. 2014. Disruptive CHD8 mutations define a subtype of autism early in development. Cell 158:263–76 [Google Scholar]
  9. Bernstein JG, Boyden ES. 2011. Optogenetic tools for analyzing the neural circuits of behavior. Trends Cogn. Sci. 15:592–600 [Google Scholar]
  10. Carneiro MO, Russ C, Ross MG, Gabriel SB, Nusbaum C, DePristo MA. 2012. Pacific biosciences sequencing technology for genotyping and variation discovery in human data. BMC Genomics 13:375 [Google Scholar]
  11. Carvill GL, Heavin SB, Yendle SC, McMahon JM, O'Roak BJ. et al. 2013a. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nat. Genet. 45:825–30 [Google Scholar]
  12. Carvill GL, Regan BM, Yendle SC, O'Roak BJ, Lozovaya N. et al. 2013b. GRIN2A mutations cause epilepsy-aphasia spectrum disorders. Nat. Genet. 45:1073–76 [Google Scholar]
  13. Carvill GL, Weckhuysen S, McMahon JM, Hartmann C, Moller RS. et al. 2014. GABRA1 and STXBP1: novel genetic causes of Dravet syndrome. Neurology 82:1245–53 [Google Scholar]
  14. Casanova J-L, Conley ME, Seligman SJ, Abel L, Notarangelo LD. 2014. Guidelines for genetic studies in single patients: lessons from primary immunodeficiencies. J. Exp. Med. 211:2137–49 [Google Scholar]
  15. Claes L, Ceulemans B, Audenaert D, Smets K, Löfgren A. et al. 2003. De novo SCN1A mutations are a major cause of severe myoclonic epilepsy of infancy. Hum. Mutat. 21:615–21 [Google Scholar]
  16. Claes L, Del-Favero J, Ceulemans B, Lagae L, Van Broeckhoven C, De Jonghe P. 2001. De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. Am. J. Hum. Genet. 68:1327–32 [Google Scholar]
  17. Cooper GM, Coe BP, Girirajan S, Rosenfeld JA, Vu TH. et al. 2011. A copy number variation morbidity map of developmental delay. Nat. Genet. 43:838–46 [Google Scholar]
  18. Cortijo S, Wardenaar R, Colomé-Tatché M, Gilly A, Etcheverry M. et al. 2014. Mapping the epigenetic basis of complex traits. Science 343:1145–48 [Google Scholar]
  19. Cross-Disorder Group of the Psychiatr. Genomics Consort., Lee SH, Ripke S, Neale BM, Faraone SV et al. 2013. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nat. Genet. 45:984–94 [Google Scholar]
  20. de Ligt J, Willemsen MH, van Bon BW, Kleefstra T, Yntema HG. et al. 2012. Diagnostic exome sequencing in persons with severe intellectual disability. N. Engl. J. Med. 367:1921–29 [Google Scholar]
  21. De Rubeis S, He X, Goldberg AP, Poultney CS, Samocha K. et al. 2014. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature 515:209–15 [Google Scholar]
  22. Derks EM, Ayub M, Chambert K, Del Favero J, Johnstone M. et al. 2013. A genome wide survey supports the involvement of large copy number variants in schizophrenia with and without intellectual disability. Am. J. Med. Genet. B Neuropsychiatr. Genet. 162B:847–54 [Google Scholar]
  23. Dibbens LM, Mullen S, Helbig I, Mefford HC, Bayly MA. et al. 2009. Familial and sporadic 15q13.3 microdeletions in idiopathic generalized epilepsy: precedent for disorders with complex inheritance. Hum. Mol. Genet. 18:3626–31 [Google Scholar]
  24. Dickson SP, Wang K, Krantz I, Hakonarson H, Goldstein DB. 2010. Rare variants create synthetic genome-wide associations. PLOS Biol. 8:e1000294 [Google Scholar]
  25. Eichten SR, Briskine R, Song J, Li Q, Swanson-Wagner R. et al. 2013. Epigenetic and genetic influences on DNA methylation variation in maize populations. Plant Cell 25:2783–97 [Google Scholar]
  26. Endele S, Rosenberger G, Geider K, Popp B, Tamer C. et al. 2010. Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes. Nat. Genet. 42:1021–26 [Google Scholar]
  27. Epi4K Consort. Epilepsy Phenome/Genome Proj 2013. De novo mutations in epileptic encephalopathies. Nature 501:217–21 [Google Scholar]
  28. Escayg A, MacDonald BT, Meisler MH, Baulac S, Huberfeld G. et al. 2000. Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS+2. Nat. Genet. 24:343–45 [Google Scholar]
  29. EuroEPINOMICS-RES Consort., Epilepsy Phenome/Genome Proj., Epi4k Consort 2014. De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies. Am. J. Hum. Genet. 95:360–70 [Google Scholar]
  30. Ewens WJ, Spielman RS. 1995. The transmission/disequilibrium test: history, subdivision, and admixture. Am. J. Hum. Genet. 57:455–64 [Google Scholar]
  31. Fellay J, Thompson AJ, Ge D, Gumbs CE, Urban TJ. et al. 2010. ITPA gene variants protect against anaemia in patients treated for chronic hepatitis C. Nature 464:405–8 [Google Scholar]
  32. Fromer M, Pocklington AJ, Kavanagh DH, Williams HJ, Dwyer S. et al. 2014. De novo mutations in schizophrenia implicate synaptic networks. Nature 506:179–84 [Google Scholar]
  33. Gleeson JG, Minnerath S, Kuzniecky RI, Dobyns WB, Young ID. et al. 2000. Somatic and germline mosaic mutations in the doublecortin gene are associated with variable phenotypes. Am. J. Hum. Genet. 67:574–81 [Google Scholar]
  34. Grayton HM, Fernandes C, Rujescu D, Collier DA. 2012. Copy number variations in neurodevelopmental disorders. Prog. Neurobiol. 99:81–91 [Google Scholar]
  35. Gulsuner S, Walsh T, Watts AC, Lee MK, Thornton AM. et al. 2013. Spatial and temporal mapping of de novo mutations in schizophrenia to a fetal prefrontal cortical network. Cell 154:518–29 [Google Scholar]
  36. Hayden EC. 2014. Technology: the $1,000 genome. Nature 507:294–95 [Google Scholar]
  37. He X, Sanders SJ, Liu L, De Rubeis S, Lim ET. 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]
  38. Heinzen EL, Radtke RA, Urban TJ, Cavalleri GL, Depondt C. et al. 2010. Rare deletions at 16p13.11 predispose to a diverse spectrum of sporadic epilepsy syndromes. Am. J. Hum. Genet. 86:707–18 [Google Scholar]
  39. Helbig I, Mefford HC, Sharp AJ, Guipponi M, Fichera M. et al. 2009. 15q13.3 microdeletions increase risk of idiopathic generalized epilepsy. Nat. Genet. 41:160–62 [Google Scholar]
  40. Heron SE, Smith KR, Bahlo M, Nobili L, Kahana E. et al. 2012. Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy. Nat. Genet. 44:1188–90 [Google Scholar]
  41. Hindorff LA, MacArthur J, Morales J, Junkins HA, Hall PN. et al. 2015. A Catalog of Published Genome-Wide Association Studies Updated Jan. 21. Natl. Hum. Genome Res. Inst., Bethesda, Md. http://www.genome.gov/gwastudies/
  42. Int. Schizophr. Consort., Purcell SM, Wray NR, Stone JL, Visscher PM et al. 2009. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460:748–52 [Google Scholar]
  43. Ionita-Laza I, Lee S, Makarov V, Buxbaum JD, Lin X. 2013. Sequence kernel association tests for the combined effect of rare and common variants. Am. J. Hum. Genet. 92:841–53 [Google Scholar]
  44. Iossifov I, O'Roak BJ, Sanders SJ, Ronemus M, Krumm N. et al. 2014. The contribution of de novo coding mutations to autism spectrum disorder. Nature 515:216–21 [Google Scholar]
  45. Iossifov I, Ronemus M, Levy D, Wang Z, Hakker I. et al. 2012. De novo gene disruptions in children on the autistic spectrum. Neuron 74:285–99 [Google Scholar]
  46. Jamuar SS, Lam AT, Kircher M, D'Gama AM, Wang J. et al. 2014. Somatic mutations in cerebral cortical malformations. N. Engl. J. Med. 371:733–43 [Google Scholar]
  47. Jiang Y, Satten GA, Han Y, Epstein MP, Heinzen EL. et al. 2014. Utilizing population controls in rare-variant case-parent association tests. Am. J. Hum. Genet. 94:845–53 [Google Scholar]
  48. Kodera H, Nakamura K, Osaka H, Maegaki Y, Haginoya K. et al. 2013. De novo mutations in SLC35A2 encoding a UDP-galactose transporter cause early-onset epileptic encephalopathy. Hum. Mutat. 34:1708–14 [Google Scholar]
  49. Kong A, Frigge ML, Masson G, Besenbacher S, Sulem P. et al. 2012. Rate of de novo mutations and the importance of father's age to disease risk. Nature 488:471–75 [Google Scholar]
  50. Kurek KC, Luks VL, Ayturk UM, Alomari AI, Fishman SJ. et al. 2012. Somatic mosaic activating mutations in PIK3CA cause CLOVES syndrome. Am. J. Hum. Genet. 90:1108–15 [Google Scholar]
  51. Lander ES. 1996. The new genomics: global views of biology. Science 274:536–39 [Google Scholar]
  52. Lee JH, Huynh M, Silhavy JL, Kim S, Dixon-Salazar T. et al. 2012. De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly. Nat. Genet. 44:941–45 [Google Scholar]
  53. Lee S, Emond MJ, Bamshad MJ, Barnes KC, Rieder MJ. et al. 2012a. Optimal unified approach for rare-variant association testing with application to small-sample case-control whole-exome sequencing studies. Am. J. Hum. Genet. 91:224–37 [Google Scholar]
  54. Lee S, Wu MC, Lin X. 2012b. Optimal tests for rare variant effects in sequencing association studies. Biostatistics 13:762–75 [Google Scholar]
  55. Lemke JR, Lal D, Reinthaler EM, Steiner I, Nothnagel M. et al. 2013. Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes. Nat. Genet. 45:1067–72 [Google Scholar]
  56. Lesca G, Rudolf G, Bruneau N, Lozovaya N, Labalme A. et al. 2013. GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction. Nat. Genet. 45:1061–66 [Google Scholar]
  57. Liu L, Sabo A, Neale BM, Nagaswamy U, Stevens C. et al. 2013. Analysis of rare, exonic variation amongst subjects with autism spectrum disorders and population controls. PLOS Genet. 9:e1003443 [Google Scholar]
  58. MacArthur DG, Balasubramanian S, Frankish A, Huang N, Morris J. et al. 2012. A systematic survey of loss-of-function variants in human protein-coding genes. Science 335:823–28 [Google Scholar]
  59. Madsen BE, Browning SR. 2009. A groupwise association test for rare mutations using a weighted sum statistic. PLOS Genet. 5:e1000384 [Google Scholar]
  60. Mardis ER. 2008. Next-generation DNA sequencing methods. Annu. Rev. Genomics Hum. Genet. 9:387–402 [Google Scholar]
  61. Margulies M, Egholm M, Altman WE, Attiya S, Bader JS. et al. 2005. Genome sequencing in microfabricated high-density picolitre reactors. Nature 437:376–80 [Google Scholar]
  62. Marini C, Scheffer IE, Nabbout R, Suls A, De Jonghe P. et al. 2011. The genetics of Dravet syndrome. Epilepsia 52:Suppl. 224–29 [Google Scholar]
  63. Marshall CR, Noor A, Vincent JB, Lionel AC, Feuk L. et al. 2008. Structural variation of chromosomes in autism spectrum disorder. Am. J. Hum. Genet. 82:477–88 [Google Scholar]
  64. McCarthy SE, Gillis J, Kramer M, Lihm J, Yoon S. 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]
  65. Mikheyev AS, Tin MM. 2014. A first look at the Oxford Nanopore MinION sequencer. Mol. Ecol. Resour. 14:1097–102 [Google Scholar]
  66. Milligan CJ, Li M, Gazina EV, Heron SE, Nair U. et al. 2014. KCNT1 gain of function in 2 epilepsy phenotypes is reversed by quinidine. Ann. Neurol. 75:581–90 [Google Scholar]
  67. Nakamura K, Kodera H, Akita T, Shiina M, Kato M. et al. 2013. De novo mutations in GNAO1, encoding a Gαo subunit of heterotrimeric G proteins, cause epileptic encephalopathy. Am. J. Hum. Genet. 93:496–505 [Google Scholar]
  68. Nava C, Dalle C, Rastetter A, Striano P, de Kovel CG. et al. 2014. De novo mutations in HCN1 cause early infantile epileptic encephalopathy. Nat. Genet. 46:640–45 [Google Scholar]
  69. Neale BM, Kou Y, Liu L, Ma'ayan A, Samocha KE. et al. 2012. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 485:242–45 [Google Scholar]
  70. Neale BM, Rivas MA, Voight BF, Altshuler D, Devlin B. et al. 2011. Testing for an unusual distribution of rare variants. PLOS Genet. 7:e1001322 [Google Scholar]
  71. Need AC, Ge D, Weale ME, Maia J, Feng S. et al. 2009. A genome-wide investigation of SNPs and CNVs in schizophrenia. PLOS Genet. 5:e1000373 [Google Scholar]
  72. Need AC, Shashi V, Hitomi Y, Schoch K, Shianna KV. et al. 2012. Clinical application of exome sequencing in undiagnosed genetic conditions. J. Med. Genet. 49:353–61 [Google Scholar]
  73. O'Roak BJ, Deriziotis P, Lee C, Vives L, Schwartz JJ. et al. 2011. Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nat. Genet. 43:585–89 [Google Scholar]
  74. O'Roak BJ, Stessman HA, Boyle EA, Witherspoon KT, Martin B. et al. 2014. Recurrent de novo mutations implicate novel genes underlying simplex autism risk. Nat. Commun. 5:5595 [Google Scholar]
  75. O'Roak BJ, Vives L, Girirajan S, Karakoc E, Krumm N. et al. 2012. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485:246–50 [Google Scholar]
  76. Ogiwara I, Ito K, Sawaishi Y, Osaka H, Mazaki E. et al. 2009. De novo mutations of voltage-gated sodium channel αII gene SCN2A in intractable epilepsies. Neurology 73:1046–53 [Google Scholar]
  77. Ohba C, Kato M, Takahashi S, Lerman-Sagie T, Lev D. et al. 2014. Early onset epileptic encephalopathy caused by de novo SCN8A mutations. Epilepsia 55:994–1000 [Google Scholar]
  78. Petrovski S, Wang Q, Heinzen EL, Allen AS, Goldstein DB. 2013. Genic intolerance to functional variation and the interpretation of personal genomes. PLOS Genet. 9:e1003709 [Google Scholar]
  79. Pierson TM, Yuan H, Marsh ED, Fuentes-Fajardo K, Adams DR. et al. 2014. GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine. Ann. Clin. Transl. Neurol. 1:190–98 [Google Scholar]
  80. Poduri A, Evrony GD, Cai X, Elhosary PC, Beroukhim R. et al. 2012. Somatic activation of AKT3 causes hemispheric developmental brain malformations. Neuron 74:41–48 [Google Scholar]
  81. Power RA, Kyaga S, Uher R, MacCabe JH, Långström N. 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]
  82. Price AL, Kryukov GV, de Bakker PI, Purcell SM, Staples J. et al. 2010. Pooled association tests for rare variants in exon-resequencing studies. Am. J. Hum. Genet. 86:832–38 [Google Scholar]
  83. Purcell SM, Moran JL, Fromer M, Ruderfer D, Solovieff N. et al. 2014. A polygenic burden of rare disruptive mutations in schizophrenia. Nature 506:185–90 [Google Scholar]
  84. Rauch A, Wieczorek D, Graf E, Wieland T, Endele S. et al. 2012. Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet 380:1674–82 [Google Scholar]
  85. Reich DE, Lander ES. 2001. On the allelic spectrum of human disease. Trends Genet. 17:502–10 [Google Scholar]
  86. Rivière JB, Mirzaa GM, O'Roak BJ, Beddaoui M, Alcantara D. et al. 2012. De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nat. Genet. 44:934–40 [Google Scholar]
  87. Roberts RJ, Carneiro MO, Schatz MC. 2013. The advantages of SMRT sequencing. Genome Biol. 14:405 [Google Scholar]
  88. Rossignol E, Kruglikov I, van den Maagdenberg AM, Rudy B, Fishell G. 2013. CaV 2.1 ablation in cortical interneurons selectively impairs fast-spiking basket cells and causes generalized seizures. Ann. Neurol. 74:209–22 [Google Scholar]
  89. Saitsu H, Kato M, Mizuguchi T, Hamada K, Osaka H. et al. 2008. De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy. Nat. Genet. 40:782–88 [Google Scholar]
  90. Samocha KE, Robinson EB, Sanders SJ, Stevens C, Sabo A. et al. 2014. A framework for the interpretation of de novo mutation in human disease. Nat. Genet. 46:944–50 [Google Scholar]
  91. Sanders SJ, Ercan-Sencicek AG, Hus V, Luo R, Murtha MT. 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]
  92. Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ. et al. 2012. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 485:237–41 [Google Scholar]
  93. Schizophr. Work. Group Psychiatr. Genomics Consort 2014. Biological insights from 108 schizophrenia-associated genetic loci. Nature 511:421–27 [Google Scholar]
  94. Sebat J, Lakshmi B, Malhotra D, Troge J, Lese-Martin C. et al. 2007. Strong association of de novo copy number mutations with autism. Science 316:445–49 [Google Scholar]
  95. Shinawi M, Schaaf CP, Bhatt SS, Xia Z, Patel A. et al. 2009. A small recurrent deletion within 15q13.3 is associated with a range of neurodevelopmental phenotypes. Nat. Genet. 41:1269–71 [Google Scholar]
  96. Shirley MD, Tang H, Gallione CJ, Baugher JD, Frelin LP. et al. 2013. Sturge–Weber syndrome and port-wine stains caused by somatic mutation in GNAQ. N. Engl. J. Med. 368:1971–79 [Google Scholar]
  97. Spira ME, Hai A. 2013. Multi-electrode array technologies for neuroscience and cardiology. Nat. Nanotechnol. 8:83–94 [Google Scholar]
  98. St Clair D, Blackwood D, Muir W, Carothers A, Walker M. et al. 1990. Association within a family of a balanced autosomal translocation with major mental illness. Lancet 336:13–16 [Google Scholar]
  99. Stefansson H, Rujescu D, Cichon S, Pietilainen OP, Ingason A. et al. 2008. Large recurrent microdeletions associated with schizophrenia. Nature 455:232–36 [Google Scholar]
  100. Thorisson GA, Smith AV, Krishnan L, Stein LD. 2005. The International HapMap Project Web site. Genome Res. 15:1592–93 [Google Scholar]
  101. Veeramah KR, O'Brien JE, Meisler MH, Cheng X, Dib-Hajj SD. et al. 2012. De novo pathogenic SCN8A mutation identified by whole-genome sequencing of a family quartet affected by infantile epileptic encephalopathy and SUDEP. Am. J. Hum. Genet. 90:502–10 [Google Scholar]
  102. Weiss LA, Escayg A, Kearney JA, Trudeau M, MacDonald BT. et al. 2003. Sodium channels SCN1A, SCN2A and SCN3A in familial autism. Mol. Psychiatry 8:186–94 [Google Scholar]
  103. Weiss LA, Shen Y, Korn JM, Arking DE, Miller DT. et al. 2008. Association between microdeletion and microduplication at 16p11.2 and autism. N. Engl. J. Med. 358:667–75 [Google Scholar]
  104. Wray NR, Purcell SM, Visscher PM. 2011. Synthetic associations created by rare variants do not explain most GWAS results. PLOS Biol. 9:e1000579 [Google Scholar]
  105. Wu MC, Kraft P, Epstein MP, Taylor DM, Chanock SJ. et al. 2010. Powerful SNP-set analysis for case-control genome-wide association studies. Am. J. Hum. Genet. 86:929–42 [Google Scholar]
  106. Wu MC, Lee S, Cai T, Li Y, Boehnke M, Lin X. 2011. Rare-variant association testing for sequencing data with the sequence kernel association test. Am. J. Hum. Genet. 89:82–93 [Google Scholar]
  107. Xu B, Ionita-Laza I, Roos JL, Boone B, Woodrick S. et al. 2012. De novo gene mutations highlight patterns of genetic and neural complexity in schizophrenia. Nat. Genet. 44:1365–69 [Google Scholar]
  108. Yang J, Lee SH, Goddard ME, Visscher PM. 2011. GCTA: a tool for genome-wide complex trait analysis. Am. J. Hum. Genet. 88:76–82 [Google Scholar]
  109. Yang Y, Muzny DM, Reid JG, Bainbridge MN, Willis A. et al. 2013. Clinical whole-exome sequencing for the diagnosis of Mendelian disorders. N. Engl. J. Med. 369:1502–11 [Google Scholar]
  110. Yuan H, Hansen KB, Zhang J, Pierson TM, Markello TC. et al. 2014. Functional analysis of a de novo GRIN2A missense mutation associated with early-onset epileptic encephalopathy. Nat. Commun. 5:3251 [Google Scholar]
  111. Zhang B, Spreafico M, Zheng C, Yang A, Platzer P. et al. 2008. Genotype-phenotype correlation in combined deficiency of factor V and factor VIII. Blood 111:5592–600 [Google Scholar]
  112. Zhu X, Need AC, Petrovski S, Goldstein DB. 2014. One gene, many neuropsychiatric disorders: lessons from Mendelian diseases. Nat. Neurosci. 17:773–81 [Google Scholar]
  113. Zuk O, Schaffner SF, Samocha K, Do R, Hechter E. et al. 2014. Searching for missing heritability: designing rare variant association studies. PNAS 111:E455–64 [Google Scholar]
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