Genome-Wide Analyses of Exonic Copy Number Variants in a Family-Based Study Point to Novel Autism Susceptibility Genes

被引:307
作者
Bucan, Maja [1 ,2 ,3 ]
Abrahams, Brett S. [4 ]
Wang, Kai [2 ,5 ]
Glessner, Joseph T. [5 ]
Herman, Edward I. [4 ]
Sonnenblick, Lisa I. [4 ]
Retuerto, Ana I. Alvarez [6 ,7 ]
Imielinski, Marcin [5 ]
Hadley, Dexter [2 ,8 ]
Bradfield, Jonathan P. [5 ]
Kim, Cecilia [5 ]
Gidaya, Nicole B. [2 ]
Lindquist, Ingrid [2 ]
Hutman, Ted [7 ]
Sigman, Marian [7 ]
Kustanovich, Vlad [1 ]
Lajonchere, Clara M. [1 ,9 ]
Singleton, Andrew [10 ]
Kim, Junhyong [3 ,8 ]
Wassink, Thomas H. [11 ]
McMahon, William M. [12 ]
Owley, Thomas [13 ]
Sweeney, John A. [13 ]
Coon, Hilary [12 ]
Nurnberger, John I., Jr. [14 ]
Li, Mingyao [15 ]
Cantor, Rita M. [1 ,16 ]
Minshew, Nancy J. [17 ]
Sutcliffe, James S. [18 ,19 ]
Cook, Edwin H. [13 ]
Dawson, Geraldine [20 ]
Buxbaum, Joseph D. [21 ,22 ,23 ,24 ]
Grant, Struan F. A. [5 ,25 ]
Schellenberg, Gerard D. [26 ]
Geschwind, Daniel H. [1 ,4 ,6 ,7 ,16 ]
Hakonarson, Hakon [5 ,25 ]
机构
[1] Autism Speaks, Autism Genet Resource Exchange, Los Angeles, CA USA
[2] Univ Penn, Dept Genet, Philadelphia, PA 19104 USA
[3] Univ Penn, Penn Ctr Bioinformat, Philadelphia, PA 19104 USA
[4] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA
[5] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA
[6] Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA USA
[7] Univ Calif Los Angeles, Ctr Autism Res, Semel Inst Neurosci & Behav, Los Angeles, CA USA
[8] Univ Penn, Dept Biol, Philadelphia, PA 19104 USA
[9] Univ So Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA
[10] NIA, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA
[11] Univ Iowa, Dept Psychiat, Iowa City, IA 52242 USA
[12] Univ Utah, Dept Psychiat, Salt Lake City, UT USA
[13] Univ Illinois, Dept Psychiat, Inst Juvenile Res, Chicago, IL 60612 USA
[14] Indiana Univ, Dept Psychiat, Indianapolis, IN 46204 USA
[15] Univ Penn, Dept Biostat, Philadelphia, PA 19104 USA
[16] Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA USA
[17] Univ Pittsburgh, Dept Psychiat & Neurol, Pittsburgh, PA USA
[18] Vanderbilt Univ, Ctr Mol Neurosci, Nashville, TN USA
[19] Vanderbilt Univ, Vanderbilt Kennedy Ctr, Nashville, TN USA
[20] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA
[21] Mt Sinai Sch Med, Seaver Autism Ctr Res & Treatment, Dept Psychiat, New York, NY USA
[22] Mt Sinai Sch Med, Seaver Autism Ctr Res & Treatment, Dept Neurosci, New York, NY USA
[23] Mt Sinai Sch Med, Seaver Autism Ctr Res & Treatment, Dept Genet, New York, NY USA
[24] Mt Sinai Sch Med, Seaver Autism Ctr Res & Treatment, Dept Genom Sci, New York, NY USA
[25] Univ Penn, Dept Pediat, Philadelphia, PA 19104 USA
[26] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA
来源
PLOS GENETICS | 2009年 / 5卷 / 06期
关键词
STRUCTURAL VARIANTS; SPECTRUM DISORDERS; CHROMOSOMAL REARRANGEMENTS; MENTAL-RETARDATION; HIGH-FREQUENCY; SCHIZOPHRENIA; DISRUPTION; PHENOTYPES; MUTATIONS; LINKAGE;
D O I
10.1371/journal.pgen.1000536
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
The genetics underlying the autism spectrum disorders (ASDs) is complex and remains poorly understood. Previous work has demonstrated an important role for structural variation in a subset of cases, but has lacked the resolution necessary to move beyond detection of large regions of potential interest to identification of individual genes. To pinpoint genes likely to contribute to ASD etiology, we performed high density genotyping in 912 multiplex families from the Autism Genetics Resource Exchange (AGRE) collection and contrasted results to those obtained for 1,488 healthy controls. Through prioritization of exonic deletions (eDels), exonic duplications (eDups), and whole gene duplication events (gDups), we identified more than 150 loci harboring rare variants in multiple unrelated probands, but no controls. Importantly, 27 of these were confirmed on examination of an independent replication cohort comprised of 859 cases and an additional 1,051 controls. Rare variants at known loci, including exonic deletions at NRXN1 and whole gene duplications encompassing UBE3A and several other genes in the 15q11-q13 region, were observed in the course of these analyses. Strong support was likewise observed for previously unreported genes such as BZRAP1, an adaptor molecule known to regulate synaptic transmission, with eDels or eDups observed in twelve unrelated cases but no controls (p = 2.3x10(-5)). Less is known about MDGA2, likewise observed to be case-specific (p = 1.3x10(-4)). But, it is notable that the encoded protein shows an unexpectedly high similarity to Contactin 4 (BLAST E-value = 3610 239), which has also been linked to disease. That hundreds of distinct rare variants were each seen only once further highlights complexity in the ASDs and points to the continued need for larger cohorts.
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