TY - JOUR
T1 - Defining the Contribution of CNTNAP2 to Autism Susceptibility
AU - Sampath, Srirangan
AU - Bhat, Shambu
AU - Gupta, Simone
AU - O'Connor, Ashley
AU - West, Andrew B.
AU - Arking, Dan E.
AU - Chakravarti, Aravinda
N1 - Funding Information:
(2) The phenotypic data and biomaterials from the National Institute of Mental Health (NIMH) Autism Genetics Initiative ( https://www.nimhgenetics.org/available _data/autism/ ) were collected with support by NIMH grants MH52708, MH39437, MH00219 and MH00980; National Health Medical Research Council grant 0034328; and by grants from the Scottish Rite, the Spunk Fund, Inc., the Rebecca and Solomon Baker Fund, the APEX Foundation, the National Alliance for Research in Schizophrenia and Affective Disorders (NARSAD), the endowment fund of the Nancy Pritzker Laboratory (Stanford); and by gifts from the Autism Society of America, the Janet M. Grace Pervasive Developmental Disorders Fund, and families and friends of individuals with autism. The Principal Investigators and co-investigators were: Neil Risch, Richard M. Myers, Donna Spiker, Linda J. Lotspeich, Joachim Hallmayer, Helena C. Kraemer, Roland D. Ciaranello, Luigi Luca Cavalli-Sforza (Stanford University, Stanford, CA); William M. McMahon and P. Brent Petersen (University of Utah, Salt Lake City, UT). The Stanford team is indebted to the parent groups and clinician colleagues who referred families and extend their gratitude to the families with individuals with autism who were partners in this research (3). The collection of data and biomaterials from the Autism Genetic Resource and the Autism Genome Research Exchange (AGRE) Consortium (http://research.agre.org/) was supported by the NIMH grant MH64547 and the Cure Autism now Foundation. The Principal Investigator was Daniel H. Geschwind (UCLA). The Co-Principal Investigators include Stanley F. Nelson and Rita Cantor (UCLA), Christa Lese Martin (U. Chicago), T. Conrad Gilliam (Columbia University); co-investigators include Maricela Alarcon (UCLA), Kenneth Lange (UCLA), Sarah J. Spence (UCLA), David H. Ledbetter (Emory University) and Hank Juo (Columbia University). Scientific oversight of the AGRE program is provided by a steering committee (Chair: Daniel H. Geschwind with members: W. Ted Brown, Maja Bucan, Joseph Buxbaum, T. Conrad Gilliam, David Greenberg, David Ledbetter, Bruce Miller, Stanley F. Nelson, Jonathan Pevsner, Carol Sprouse, Gerard Schellenberg, Rudolph Tanzi).
Funding Information:
CNTNAP2 gene expression study was supported by a grant from the Simons Foundation (SFARI 137603 to DEA ). Tissue was generously provided by the NICHD Brain and Tissue Bank for Developmental Disorders at the University of Maryland, Baltimore, MD, the Autism Tissue Program, and Harvard Brain Tissue Resource Center (supported in part by PHS grant R24 MH068855). The goal of these centers is to distribute tissue, and, therefore, cannot endorse the studies performed or the interpretation of results. We thank the contributing families for their enormous generosity and support of research in autism. We thank Jane Pickett and Ellen Xiu for coordinating efforts for tissue collection.
PY - 2013/10/17
Y1 - 2013/10/17
N2 - Multiple lines of genetic evidence suggest a role for CNTNAP2 in autism. To assess its population impact we studied 2148 common single nucleotide polymorphisms (SNPs) using transmission disequilibrium test (TDT) across the entire ~3.3 Mb CNTNAP2 locus in 186 (408 trios) multiplex and 323 simplex families with autistic spectrum disorder (ASD). This analysis yielded two SNPs with nominal statistical significance (rs17170073, p = 2.0 x 10-4; rs2215798, p = 1.6 x 10-4) that did not survive multiple testing. In a combined analysis of all families, two highly correlated (r2 = 0.99) SNPs in intron 14 showed significant association with autism (rs2710093, p = 9.0 x 10-6; rs2253031, p = 2.5 x 10-5). To validate these findings and associations at SNPs from previous autism studies (rs7794745, rs2710102 and rs17236239) we genotyped 2051 additional families (572 multiplex and 1479 simplex). None of these variants were significantly associated with ASD after corrections for multiple testing. The analysis of Mendelian errors within each family did not indicate any segregating deletions. Nevertheless, a study of CNTNAP2 gene expression in brains of autistic patients and of normal controls, demonstrated altered expression in a subset of patients (p = 1.9 x10-5). Consequently, this study suggests that although CNTNAP2 dysregulation plays a role in some cases, its population contribution to autism susceptibility is limited.
AB - Multiple lines of genetic evidence suggest a role for CNTNAP2 in autism. To assess its population impact we studied 2148 common single nucleotide polymorphisms (SNPs) using transmission disequilibrium test (TDT) across the entire ~3.3 Mb CNTNAP2 locus in 186 (408 trios) multiplex and 323 simplex families with autistic spectrum disorder (ASD). This analysis yielded two SNPs with nominal statistical significance (rs17170073, p = 2.0 x 10-4; rs2215798, p = 1.6 x 10-4) that did not survive multiple testing. In a combined analysis of all families, two highly correlated (r2 = 0.99) SNPs in intron 14 showed significant association with autism (rs2710093, p = 9.0 x 10-6; rs2253031, p = 2.5 x 10-5). To validate these findings and associations at SNPs from previous autism studies (rs7794745, rs2710102 and rs17236239) we genotyped 2051 additional families (572 multiplex and 1479 simplex). None of these variants were significantly associated with ASD after corrections for multiple testing. The analysis of Mendelian errors within each family did not indicate any segregating deletions. Nevertheless, a study of CNTNAP2 gene expression in brains of autistic patients and of normal controls, demonstrated altered expression in a subset of patients (p = 1.9 x10-5). Consequently, this study suggests that although CNTNAP2 dysregulation plays a role in some cases, its population contribution to autism susceptibility is limited.
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U2 - 10.1371/journal.pone.0077906
DO - 10.1371/journal.pone.0077906
M3 - Article
C2 - 24147096
AN - SCOPUS:84885750845
SN - 1932-6203
VL - 8
JO - PloS one
JF - PloS one
IS - 10
M1 - e77906
ER -