A genome-wide linkage and association scan reveals novel loci for autism

Weiss, Lauren A.; Arking, Dan E.; Daly, Mark J.; Chakravarti, Aravinda; Brune, Camille W.; West, Kristen M.; O’Connor, Ashley; Hilton, Gina M.; Tomlinson, Rebecca L.; West, Andrew B.; Cook, Edwin H.; Green, Todd; Chang, Shun Chiao; Gabriel, Stacey; Gates, Casey; Hanson, Ellen; Kirby, Andrew; Korn, Joshua M.; Kuruvilla, Finny G.; McCarroll, Steven A.; Morrow, Eric M.; Neale, Benjamin M.; Purcell, Shaun; Sasanfar, Roksana; Sougnez, Carrie; Stevens, Christine; Altshuler, David; Gusella, James F.; Santangelo, Susan L.; Sklar, Pamela; Tanzi, Rudolph E.; Anney, Richard; Bailey, Anthony; Baird, Gillian; Battaglia, Agatino; Berney, T. P.; Betancur, Catalina; Bölte, Sven; Bolton, Patrick; Brian, Jessica; Bryson, Susan E.; Buxbaum, Joseph D.; Cabrito, Inês; Cai, Guiqing; Cantor, Rita M.; Coon, Hilary; Conroy, Judith; Correia, Catarina; Corsello, Christina; Crawford, Emily L.; Cuccaro, Michael L.; Dawson, Geraldine; Jonge, Maretha de; Devlin, Bernie; Duketis, Eftichia; Ennis, Sean; Estes, Annette; Farrar, Penny; Fombonne, Éric; Freitag, Christine M.; Gallagher, Louise; Geschwind, Daniel H.; Gilbert, John R.; Gill, Michael; Gillberg, Christopher; Goldberg, Jeremy; Green, Andrew; Green, Jonathan; Guter, Stephen J.; Haines, Jonathan L.; Hallmayer, Joachim; Hus, Vanessa; Klauck, Sabine M.; Korvatska, Olena; Lamb, Janine A.; Laskawiec, Magdalena; Leboyer, Marion; Couteur, Ann Le; Leventha, Bennett L.; Liu, Xiao Qing; Lord, Catherine; Lotspeich, Linda; Maestrini, Elena; Magalhães, Tiago R.; Mahoney, William M.; Mantoulan, Carine; McConachie, Helen; McDougle, Christopher J.; McMahon, William M.; Marshall, Christian R.; Miller, Judith; Minshew, Nancy J.; Monaco, Anthony P.; Munson, Jeff; Nürnberger, John I.; Oliveira, Guiomar; Pagnamenta, Alistair T.; Papanikolaou, Κaterina; Parr, Jeremy; Paterson, Andrew D.; Pericak‐Vance, Margaret A.; Pickles, Andrew; Pinto, Dalila; Piven, Joseph; Posey, David J.; Poustka, Annemarie; Poustka, Fritz; Regan, Regina; Reichert, Jennifer; Renshaw, Katy; Roberts, Wendy; Rogé, Bernadette; Rutter, Michael; Salt, Jeff; Schellenberg, Gerard D.; Scherer, Stephen W.; Sheffield, Val C.; Sutcliffe, James S.; Szatmári, Péter; Tansey, Katherine E.; Thompson, Ann; Tsiantis, John; Engeland, Hermán van; Vicente, Astrid M.; Vieland, Veronica J.; Volkmar, Fred R.; Wallace, Simon; Wassink, Thomas H.; Wijsman, Ellen M.; Wing, Kirsty; Wittemeyer, Kerstin; Yaspan, Brian L.; Zwaigenbaum, Lonnie; Yoo, Seung Yun; Hill, Robert S.; Mukaddes, Nahit Motavallı; Balkhy, Soher; Gascon, Generoso G.; Al-Saad, Samira; Hashmi, Asif; Ware, Janice; Joseph, Robert M.; LeClair, Elaine; Partlow, Jennifer N.; Barry, Brenda J.; Walsh, Christopher A.; Pauls, David L.; Moilanen, Irma; Ebeling, Hanna; Mattila, Marja Leena; Kuusikko, Sanna; Jussila, Katja; Ignatius, Jaakko; Tolouei, Ala; Ghadami, Majid; Rostami, Maryam; Hosseinipour, Azam; Valujerdi, Maryam; Andresen, Kara; Winkloski, Brian; Haddad, Stephen A.; Kunkel, Lou; Kohane, Zak; Tran, Tram; Kong, Sek Won; O'Neil, Stephanie Brewster; Hundley, Rachel; Holm, Ingrid A.; Peters, Heather; Baroni, Elizabeth; Cangialose, Aislyn; Jackson, Lindsay; Albers, Lisa; Becker, Ronald E.; Bridgemohan, Carolyn; Friedman, Sandra; Münir, Kerim; Nazir, Ramzi; Palfrey, Judith S.; Schonwald, Alison; Simmons, Esau; Rappaport, Leonard; Gauthier, Julie; Mottron, Laurent; Joober, Ridha; Rouleau, Guy A.; Rehnström, Karola; Wendt, Lennart von; Peltonen, Leena

doi:10.1038/nature08490

Cited by 571 publications

(489 citation statements)

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“…Finally, using genome-wide linkage analysis and association scans, a SNP located on chromosome 5p15 between SEMA5A and TAS2R1, was significantly associated with autism [Weiss et al, 2009]. Subsequently, reduced expression of SEMA5A in brains from autistic patients implicated SEMA5A as an autism susceptibility gene.…”

Section: Discussionmentioning

confidence: 99%

Biallelic SEMA3A defects cause a novel type of syndromic short stature

Hofmann

Zweier

Sticht

et al. 2013

American J of Med Genetics Pt A

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Chromosomal microarray testing is commonly used to identify disease causing de novo copy number variants in patients with developmental delay and multiple congenital anomalies. In such a patient we now observed an 150 kb deletion on chromosome 7q21.11 affecting the first exon of the axon guidance molecule gene SEMA3A (sema domain, immunoglobulin domain (Ig), short basic domain, secreted, (semaphorin) 3A). This deletion was inherited from the healthy father, but considering the function of SEMA3A and phenotypic similarity to the knock‐out mice, we still assumed a pathogenic relevance and tested for a recessive second defect. Sequencing of SEMA3A in the patient indeed revealed the de novo in‐frame mutation p.Phe316_Lys317delinsThrSerSerAsnGlu. Cloning of the mutated allele in combination with two informative SNPs confirmed compound heterozygosity in the patient. While the altered protein structure was predicted to be benign, aberrant splicing resulting in a premature stop codon was proven by RT‐PCR to occur in about half of the transcripts from this allele. Expression profiling in human fetal and adult cDNA panels, confirmed a high expression of SEMA3A in all brain regions as well as in adult and fetal heart and fetal skeletal muscle. Normal intellectual development in the patient was surprising but may be explained by the remaining 20% of SEMA3A expression level demonstrated by quantitative RT‐PCR. We therefore report a novel autosomal recessive syndrome characterized by postnatal short stature with relative macrocephaly, camptodactyly, septal heart defect and several minor anomalies caused by biallelic mutations in SEMA3A. © 2013 Wiley Periodicals, Inc.

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Section: Discussionmentioning

confidence: 99%

Biallelic SEMA3A defects cause a novel type of syndromic short stature

Hofmann

Zweier

Sticht

et al. 2013

American J of Med Genetics Pt A

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“…The original sample was comprised of 801 ASD nuclear families (3,000 individuals) from the Autism Genetic Resource Exchange (AGRE) repository [Geschwind et al, 2001], who were genotyped as a part of a GWA study [Weiss et al, 2009].…”

Section: Materials and Methods Study Samplementioning

confidence: 99%

Sex‐specific association of a common variant of the XG gene with autism spectrum disorders

Chang

Pauls

Lange

et al. 2013

American J of Med Genetics Pt B

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Autism spectrum disorders (ASD) are much more common in males than in females. Studies using both linkage and candidate gene association approaches have identified genetic variants specific to families in which all affected cases were male, suggesting that sex may interact with or otherwise influence the expression of specific genes in association with ASD. In this study, we specifically evaluated the sex-specific genetic effects of ASD with a family-based genome-wide association study approach using the data from the Autism Genetic Resource Exchange repository. We evaluated the male-specific genetic effects of ASD in 374 multiplex families of European ancestry in which all affected were male (male-only; MO) and identified a novel genome-wide significant association in the pseudoautosomal boundary on chromosome Xp22.33/Yp11.31 in the MO families of predominantly paternal origin (rs2535443, p ¼ 3.8 Â 10 À8 ). Five markers that reside within a 550 kb intergenic region on chromosome 13q33.3, between the MYO16 and IRS2 genes, also showed suggestive association with ASD in the MO families (p ¼ 3.3 Â 10 À5 to 5.3 Â 10 À7 ). In contrast, none of these markers appeared to be associated with ASD in the families containing any affected females. Our results suggest that the pseudoautosomal boundary on Xp22.33/Yp11.31 may harbor male-specific genetic variants for ASD. Ó 2013 Wiley Periodicals, Inc.Key words: autism; GWAS; sex-specific; pseudoautosomal INTRODUCTIONAutism spectrum disorders (ASD) are neurodevelopmental disorders characterized by clinical symptoms of diverse impairments in social interactions, reciprocal communication, and repetitive and stereotyped patterns of behaviors and interests. Numerous studies have affirmed the heritability of ASDs. Evidence indicates that ASD has complex inheritance patterns [Bailey et al., 1995;Fombonne, 2005;Lauritsen et al., 2005;Freitag, 2007]. Yet despite the high heritability estimate of over 90% [Bailey et al., 1995], genetic variants that have been reported to be associated with ASD have either failed to be replicated or accounted for only a small proportion of cases [Santangelo and Tsatsanis, 2005]. Furthermore, the wide range of clinical manifestations of ASD suggests that it may in fact comprise multiple disorders that have separate etiologies but share behavioral commonalities. This phenotypic heterogeneity How to Cite this Article: 742Neuropsychiatric Genetics may imply genetic heterogeneity and may at least partially explain the limited success in consistently identifying common genetic variants of ASD in prior studies. Recent studies suggest that approximately 10-15% of ASD may be due to genetic syndromes with known comorbidities with ASD (e.g., fragile X syndrome, tuberous sclerosis) or rare chromosomal abnormalities [Folstein and Rosen-Sheidley, 2001;Freitag, 2007], while the etiology of the majority of familial ASD cases remains unclear. One potentially more efficient approach to identify susceptibility loci for ASD is to separate samples into more homogenous subgr...

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“…SHANK3 is involved in (i) synapse formation and maturation, (ii) the link between neurotransmitter receptors and ion channels, and (iii) the interaction with scaffolding proteins and gene regulatory proteins (e.g., protein of chromatin remodeling CHD8; Anney et al., 2010; Cotney et al., 2015; De Rubeis et al., 2014; O'Roak et al., 2011). NRXN1 , NLGN3/4X, and SHANK3 genes, which encode proteins involved in neuronal cell adhesion and in the regulation of synaptic transmission, are considered strong candidate loci for ASD (Weiss & Arking, 2009). Variations in those loci have also been detected in several patients with ASD (Anney et al., 2010; O'Roak et al., 2011; Table 1).…”

Section: Reviewmentioning

confidence: 99%

Autism throughout genetics: Perusal of the implication of ion channels

et al. 2018

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BackgroundAutism spectrum disorder (ASD) comprises a group of neurodevelopmental psychiatric disorders characterized by deficits in social interactions, interpersonal communication, repetitive and stereotyped behaviors and may be associated with intellectual disabilities. The description of ASD as a synaptopathology highlights the importance of the synapse and the implication of ion channels in the etiology of these disorders.MethodsA narrative and critical review of the relevant papers from 1982 to 2017 known by the authors was conducted.ResultsGenome‐wide linkages, association studies, and genetic analyses of patients with ASD have led to the identification of several candidate genes and mutations linked to ASD. Many of the candidate genes encode for proteins involved in neuronal development and regulation of synaptic function including ion channels and actors implicated in synapse formation. The involvement of ion channels in ASD is of great interest as they represent attractive therapeutic targets. In agreement with this view, recent findings have shown that drugs modulating ion channel function are effective for the treatment of certain types of patients with ASD.ConclusionThis review describes the genetic aspects of ASD with a focus on genes encoding ion channels and highlights the therapeutic implications of ion channels in the treatment of ASD.

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A genome-wide linkage and association scan reveals novel loci for autism

Cited by 571 publications

References 40 publications

Biallelic SEMA3A defects cause a novel type of syndromic short stature

Biallelic SEMA3A defects cause a novel type of syndromic short stature

Sex‐specific association of a common variant of the XG gene with autism spectrum disorders

Autism throughout genetics: Perusal of the implication of ion channels

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