Abstract
Copy number variation has emerged as an important cause of phenotypic variation, particularly in relation to some complex disorders. Autism spectrum disorder (ASD) is one such disorder, in which evidence is emerging for an etiological role for some rare penetrant de novo and rare inherited copy number variants (CNVs). De novo variation, however, does not always explain the familial nature of ASD, leaving a gap in our knowledge concerning the heritable genetic causes of this disorder. Extended pedigrees, in which several members have ASD, provide an opportunity to investigate inherited genetic risk factors. In this current study, we recruited 19 extended ASD pedigrees, and, using the Illumina HumanOmni2.5 BeadChip, conducted genome-wide CNV interrogation. We found no definitive evidence of an etiological role for segregating CNVs in these pedigrees, and no evidence that linkage signals in these pedigrees are explained by segregating CNVs. However, a small number of putative de novo variants were transmitted from BAP parents to their ASD offspring, and evidence emerged for a rare duplication CNV at 11p13.3 harboring two putative ‘developmental/neuropsychiatric’ susceptibility gene(s), GSTP1 and NDUFV1.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Abrahams BS, Geschwind DH (2008) Advances in autism genetics: on the threshold of a new neurobiology. Nat Rev Genet 9:341–355
Allen-Brady K, Miller J, Matsunami N, Stevens J, Block H, Farley M, Krasny L, Pingree C, Lainhart J, Leppert M et al (2009) A high-density SNP genome-wide linkage scan in a large autism extended pedigree. Mol Psychiatry 14:590–600
American Psychiatric Association (APA) (2000) DSM-IV Diagnostic and Statistical Manual of Mental Disorders, 4th edn, text revision. APA, Washington, DC
Anney R, Klei L, Pinto D, Almeida J, Bacchelli E, Baird G, Bolshakova N, Bölte S, Bolton PF, Bourgeron T et al (2012) Individual common variants exert weak effects on the risk for autism spectrum disorders. Hum Mol Gen 21:4781–4792
Bailey A, Le Couteur A, Gottesman I, Bolton P, Simonoff E, Yuzda E, Rutter M (1995) Autism as a strongly genetic disorder: evidence from a British twin study. Psychol Med 25:63–77
Banerjee-Basu S, Packer A (2010) SFARI gene: an evolving database for the autism research community. Dis Models Mechanisms 3:133–135
Ben-Shachar D (2009) Mitochondrial complex I as a possible novel peripheral biomarker for Schizophrenia. In: Ritsner Michael S (ed) The handbook of neuropsychiatric biomarkers, endophenotypes and genes, vol 3. Springer, New York, pp 71–82
Bierut LJ, Agrawal A, Bucholz KK, Doheny KF, Laurie C, Pugh E, Fisher S, Fox L, Howells W, Bertelsen S et al (2010) A genome-wide association study of alcohol dependence. Proc Natl Acad Sci 107:5082–5087
Bolton P, MacDonald H, Pickles A, Rios P, Goode S, Crowson M, Bailey A, Rutter M (1994) A case–control family history study of autism. J Child Psychol Psychiatry 35:877–900
Buxbaum JD, Daly MJ, Devlin B, Lehner T, Roeder K, State MW (2012) The autism sequencing consortium: large-scale, high-throughput sequencing in autism spectrum disorders. Neuron 76:1052–1056
Colella S, Yau C, Taylor JM, Mirza G, Butler H, Clouston P, Bassett AS, Seller A, Holmes CC, Ragoussis J (2007) QuantiSNP: an Objective Bayes Hidden-Markov Model to detect and accurately map copy number variation using SNP genotyping data. Nucleic Acids Res 35:2013–2025
Devlin B, Scherer SW (2012) Genetic architecture in autism spectrum disorder. Curr Opin Genet Dev 22(3):229–237
Disciglio V, Rizzo C, Mencarelli MA, Mucciolo M, Marozza A, Di Marco C, Massarelli A, Canocchi V, Baldassarri M, Ndoni E et al (2014) Interstitial 22q13 deletions not involving SHANK3 gene: a new contiguous gene syndrome. Am J Med Genet Part A 164(7):1666–1676
Firth HV, Richards SM, Bevan AP, Clayton S, Corpas M, Rajan D, Van Vooren S, Moreau Y, Pettett RM, Carter NP (2009) DECIPHER: database of chromosomal imbalance and phenotype in humans using ensembl resources. Am J Hum Genet 84:524–533
Frazier TW, Thompson L, Youngstrom EA, Law P, Hardan AY, Eng C, Morris N (2014) A twin study of heritable and shared environmental contributions to autism. J Autism Dev Disord 44:2013–2025
Gibbs RA, Belmont JW, Hardenbol P, Willis TD, Yu F, Yang H, Ch’ang L-Y, Huang W, Liu B, Shen Y et al (2003) The international HapMap project. Nature 426:789–796
Goh S, Dong Z, Zhang Y, DiMauro S, Peterson BS (2014) Mitochondrial dysfunction as a neurobiological subtype of autism spectrum disorder: evidence from brain imaging. JAMA psychiatry 71(6):665–671
Gravina P, Spoletini I, Masini S, Valentini A, Vanni D, Paladini E, Bossù P, Caltagirone C, Federici G, Spalletta G et al (2011) Genetic polymorphisms of glutathione-S-transferases GSTM1, GSTT1, GSTP1 and GSTA1 as risk factors for schizophrenia. Psychiatry Res 187:454–456
Haas RH (2010) Autism and mitochondrial disease. Dev Dis Res Reviews 16:144–153
Hallmayer J, Cleveland S, Torres A, Phillips J, Cohen B, Torigoe T, Miller J, Fedele A, Collins J, Smith K et al (2011) Genetic heritability and shared environmental factors among twin pairs with autism. Arch Gen Psychiatry 68(11):1095–1102
Hämäläinen RH, Avela K, Lambert JA, Kallijärvi J, Eyaid W, Gronau J, Ignaszewski AP, McFadden D, Sorge G, Lipsanen-Nyman M et al (2004) Novel mutations in the TRIM37 gene in Mulibrey Nanism. Hum Mutat 23:522
Hurley RS, Losh M, Parlier M, Reznick JS, Piven J (2007) The broad autism phenotype questionnaire. J Autism Dev Disord 37:1679–1690
Lavelle TA, Weinstein MC, Newhouse JP, Munir K, Kuhlthau KA, Prosser LA (2014) Economic burden of childhood autism spectrum disorders. Pediatrics 133(3):e520–e529
Leggett V, Jacobs P, Nation K, Scerif G, Bishop DV (2010) Neurocognitive outcomes of individuals with a sex chromosome trisomy: XXX, XYY, or XXY: a systematic review. Dev Med Child Neurol 52:119–129
Lichtenstein P, Carlström E, Råstam M, Gillberg C, Anckarsäter H (2010) The genetics of autism spectrum disorders and related neuropsychiatric disorders in childhood. Am J Psychiatry 167:1357–1363
Lord C, Rutter M, Le Couteur A (1994) Autism diagnostic interview–revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. J Autism Dev Disord 24:659–685
Lord C, Risi S, Lambrecht L, Cook EH, Leventhal BL, DiLavore PC, Pickles A, Rutter M (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 30:205–223
Losh M, Adolphs R, Poe MD, Couture S, Penn D, Baranek GT, Piven J (2009) Neuropsychological profile of autism and the broad autism phenotype. Arch Gen Psychiatry 66:518–526
Marin SE, Mesterman R, Robinson B, Rodenburg RJ, Smeitink J, Tarnopolsky MA (2013) Leigh syndrome associated with mitochondrial complex I deficiency due to novel mutations In NDUFV1 and NDUFS2. Gene 516:162–167
Marshall CR, Noor A, Vincent JB, Lionel AC, Feuk L, Skaug J, Shago M, Moessner R, Pinto D, Ren Y et al (2008) Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet 82:477–488
Marui T, Funatogawa I, Koishi S, Yamamoto K, Matsumoto H, Hashimoto O, Jinde S, Nishida H, Sugiyama T, Kasai K et al (2011) The NADH-ubiquinone oxidoreductase 1 alpha subcomplex 5 (NDUFA5) gene variants are associated with autism. Acta Psychiatr Scand 123:118–124
Matsunami N, Hensel CH, Baird L, Stevens J, Otterud B, Leppert T, Varvil T, Hadley D, Glessner JT, Pellegrino R et al (2014) Identification of rare DNA sequence variants in high-risk autism families and their prevalence in a large case/control population. Mol Autism 5:5
Neale BM, Kou Y, Liu L, Ma’ayan A, Samocha KE, Sabo A, Lin CF, Stevens C, Wang LS, Makarov V et al (2012) Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 485:242–245
Noor A, Whibley A, Marshall CR, Gianakopoulos PJ, Piton A, Carson AR, Orlic-Milacic M, Lionel AC, Sato D, Pinto D et al (2010) Disruption at the PTCHD1 Locus on Xp22.11 in Autism spectrum disorder and intellectual disability. Sci Trans Med 2(49):49ra68
Nordenbæk C, Jørgensen M, Kyvik KO, Bilenberg N (2014) A Danish population-based twin study on autism spectrum disorders. Eur Child Adolesc Psychiatry 23:35–43
O’Roak BJ, Vives L, Girirajan S, Karakoc E, Krumm N, Coe BP, Levy R, Ko A, Lee C, Smith JD et al (2012) Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485:246–250
Pagnamenta AT, Khan H, Walker S, Gerrelli D, Wing K, Bonaglia MC, Giorda R, Berney T, Mani E, Molteni M et al (2011) Rare familial 16q21 microdeletions under a linkage peak implicate cadherin 8 (CDH8) in susceptibility to autism and learning disability. J Med Genet 48:48–54
Park C, Park SK (2012) Molecular links between mitochondrial dysfunctions and schizophrenia. Mol Cells 33:105–110
Pinto D, Pagnamenta AT, Klei L, Anney R, Merico D, Regan R, Conroy J, Magalhaes TR, Correia C, Abrahams BS et al (2010) Functional impact of global rare copy number variation in autism spectrum disorders. Nature 466:368–372
Pinto D, Darvishi K, Shi X, Rajan D, Rigler D, Fitzgerald T, Lionel AC, Thiruvahindrapuram B, MacDonald JR, Mills R, Prasad A, Noonan K et al (2011) Comprehensive assessment of array-based platforms and calling algorithms for detection of copy number variants. Nat Biotechnol 29(6):512–520
Pinto D, Delaby E, Merico D, Barbosa M, Merikangas A, Klei L, Thiruvahindrapuram B, Xu X, Ziman R, Wang Z et al (2014) Convergence of genes and cellular pathways dysregulated in autism spectrum disorders. Am J Hum Genet 94:677–694
Piven J, Gayle J, Chase GA, Fink B, Landa R, Wzorek MM, Folstein SE (1990) A family history study of neuropsychiatric disorders in the adult siblings of autistic individuals. J Am Acad Child Adolesc Psychiatry 29:177–183
Piven J, Palmer P, Landa R, Santangelo S, Jacobi D, Childress D (1997) Personality and language characteristics in parents from multiple-incidence autism families. Am J Med Genet 74:398–411
Piven J, Vieland VJ, Parlier M, Thompson A, O’Conner I, Woodbury-Smith M, Huang Y, Walters KA, Fernandez B, Szatmari P (2013) A molecular genetic study of autism and related phenotypes in extended pedigrees. J Neurodev Dis 5:30
Prasad A, Merico D, Thiruvahindrapuram B, Wei J, Lionel AC, Sato D, Rickaby J, Lu C, Szatmari P, Roberts W et al (2012) A discovery resource of rare copy number variations in individuals with autism spectrum disorder. G3 2:1665–1685
Risheg H, Pasion R, Sacharow S, Proud V, Immken L, Schwartz S, Tepperberg JH, Papenhausen P, Tan TY, Andrieux J et al (2013) Clinical comparison of overlapping deletions of 19p13. 3. Am J Med Genet Part A 161:1110–1116
Risi S, Lord C, Gotham K, Corsello C, Chrysler C, Szatmari P, Cook EH Jr, Leventhal BL, Pickles A (2006) Combining information from multiple sources in the diagnosis of autism spectrum disorders. J Am Acad Child Adolesc Psychiatry 45:1094–1103
Sabbir MG, Wigle N, Loewen S, Gu Y, Buse C, Hicks GG, Mowat MR (2010) Identification and characterization of Dlc1 isoforms in the mouse and study of the biological function of a single gene trapped isoform. BMC Biol 8:17
Salyakina D, Cukier HN, Lee JM, Sacharow S, Nations LD, Ma D, Jaworski JM, Konidari I, Whitehead PL, Wright HH et al (2011) Copy number variants in extended autism spectrum disorder families reveal candidates potentially involved in autism risk. PloS One 6:e26049
Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ, Willsey AJ, Ercan-Sencicek AG, DiLullo NM, Parikshak NN, Stein JL et al (2012) De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 485:237–241
Sato D, Lionel AC, Leblond CS, Prasad A, Pinto D, Walker S, O’Connor I, Russell C, Drmic IE, Hamdan FF et al (2012) SHANK1 Deletions in Males with Autism Spectrum Disorder. Am J Hum Genet 90(5):879–887
Shi L, Zhang X, Golhar R, Otieno FG, He M, Hou C, Kim C, Keating B, Lyon GJ, Wang K et al (2013) Whole-genome sequencing in an autism multiplex family. Mol Autism 4:8
Szatmari P, Paterson AD, Zwaigenbaum L, Roberts W, Brian J, Liu XQ, Vincent JB, Skaug JL, Thompson AP, Senman L et al (2007) Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat Genet 39:319–328
Tew KD, Manevich Y, Grek C, Xiong Y, Uys J, Townsend DM (2011) The role of glutathione-S-transferase P in signaling pathways and S-glutathionylation in cancer. Free Radic Biol Med 51:299–313
Uddin M, Tammimies K, Pellecchia G, Alipanahi B, Hu P, Wang Z, Pinto D, Lau L, Nalpathamkalam T, Marshall CR et al (2014) Brain-expressed exons under purifying selection are enriched for de novo mutations in autism spectrum disorder. Nat Genet 46(7):742–747
Vieland VJ, Hallmayer J, Huang Y, Pagnamenta AT, Pinto D, Khan H, Monaco AP, Paterson AD, Scherer SW, Sutcliffe JS et al (2011) Novel method for combined linkage and genome-wide association analysis finds evidence of distinct genetic architecture for two subtypes of autism. J Neurodev Dis 3(2):113–123
Wang K, Li M, Hadley D, Liu R, Glessner J, Grant SF, Hakonarson H, Bucan M (2007) PennCNV: an integrated hidden Markov model designed for high-resolution copy number variation detection in whole-genome SNP genotyping data. Genome Res 17:1665–1674
Wichmann H, Gieger C, Illig T, MONICA/KORA Study Group (2005) KORA-gen-resource for population genetics, controls and a broad spectrum of disease phenotypes. Gesundheitswesen 67:S26
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
Acknowledgments
We thank the families for their participation in the study and The Centre for Applied Genomics at the Hospital for Sick Children and University of Toronto for technical support. MWS acknowledges the support of CIHR [Strategic Training in Advanced Epidemiology (STAGE) program], Hamilton Health Sciences, and Scottish Rite Charitable Foundation. This work was funded in part by CIHR operating grants #79499 and #89777, NIH grants MH076028, HD003110 (JP) and MH086117 (VJV). SWS holds the GlaxoSmithKline-CIHR Endowed Chair in Genome Sciences. PS holds the Patsy and Jamie Anderson Chair in Child and Youth Mental Health.This study makes use of data generated by the DECIPHER Consortium. A full list of centers who contributed to the generation of the data is available from http://decipher.sanger.ac.uk and via email from decipher@sanger.ac.uk. Funding for the project was provided by the Wellcome Trust.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Woodbury-Smith, M., Paterson, A.D., Thiruvahindrapduram, B. et al. Using extended pedigrees to identify novel autism spectrum disorder (ASD) candidate genes. Hum Genet 134, 191–201 (2015). https://doi.org/10.1007/s00439-014-1513-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00439-014-1513-6