Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes

Maja Bucan, Brett S. Abrahams, Kai Wang, Joseph T. Glessner, Edward I. Herman, Lisa I. Sonnenblick, Ana I. Alvarez Retuerto, Marcin Imielinski, Dexter Hadley, Jonathan P. Bradfield, Cecilia Kim, Nicole B. Gidaya, Ingrid Lindquist, Ted Hutman, Marian Sigman, Vlad Kustanovich, Clara M. Lajonchere, Andrew Singleton, Junhyong Kim, Thomas H. Wassink & 16 others William M. McMahon, Thomas Owley, John A. Sweeney, Hilary Coon, John I. Nurnberger, Mingyao Li, Rita M. Cantor, Nancy J. Minshew, James S. Sutcliffe, Edwin H. Cook, Geraldine Dawson, Joseph D. Buxbaum, Struan F A Grant, Gerard D. Schellenberg, Daniel H. Geschwind, Hakon Hakonarson

Research output: Contribution to journalArticle

278 Citations (Scopus)

Abstract

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 = 2.3×10-5). Less is known about MDGA2, likewise observed to be case-specific (p = 1.3×10-4). But, it is notable that the encoded protein shows an unexpectedly high similarity to Contactin 4 (BLAST E-value = 3×10-39), 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.

Original languageEnglish (US)
Article numbere1000536
JournalPLoS Genetics
Volume5
Issue number6
DOIs
StatePublished - Jun 2009
Externally publishedYes

Fingerprint

Autistic Disorder
genome
Genome
Gene Duplication
gene
gene duplication
Genes
Contactins
genes
synaptic transmission
loci
prioritization
genetic resources
Synaptic Transmission
genotyping
etiology
genetic resource
autism
family
Autism Spectrum Disorder

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Bucan, M., Abrahams, B. S., Wang, K., Glessner, J. T., Herman, E. I., Sonnenblick, L. I., ... Hakonarson, H. (2009). Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes. PLoS Genetics, 5(6), [e1000536]. https://doi.org/10.1371/journal.pgen.1000536

Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes. / Bucan, Maja; Abrahams, Brett S.; Wang, Kai; Glessner, Joseph T.; Herman, Edward I.; Sonnenblick, Lisa I.; Alvarez Retuerto, Ana I.; Imielinski, Marcin; Hadley, Dexter; Bradfield, Jonathan P.; Kim, Cecilia; Gidaya, Nicole B.; Lindquist, Ingrid; Hutman, Ted; Sigman, Marian; Kustanovich, Vlad; Lajonchere, Clara M.; Singleton, Andrew; Kim, Junhyong; Wassink, Thomas H.; McMahon, William M.; Owley, Thomas; Sweeney, John A.; Coon, Hilary; Nurnberger, John I.; Li, Mingyao; Cantor, Rita M.; Minshew, Nancy J.; Sutcliffe, James S.; Cook, Edwin H.; Dawson, Geraldine; Buxbaum, Joseph D.; Grant, Struan F A; Schellenberg, Gerard D.; Geschwind, Daniel H.; Hakonarson, Hakon.

In: PLoS Genetics, Vol. 5, No. 6, e1000536, 06.2009.

Research output: Contribution to journalArticle

Bucan, M, Abrahams, BS, Wang, K, Glessner, JT, Herman, EI, Sonnenblick, LI, Alvarez Retuerto, AI, Imielinski, M, Hadley, D, Bradfield, JP, Kim, C, Gidaya, NB, Lindquist, I, Hutman, T, Sigman, M, Kustanovich, V, Lajonchere, CM, Singleton, A, Kim, J, Wassink, TH, McMahon, WM, Owley, T, Sweeney, JA, Coon, H, Nurnberger, JI, Li, M, Cantor, RM, Minshew, NJ, Sutcliffe, JS, Cook, EH, Dawson, G, Buxbaum, JD, Grant, SFA, Schellenberg, GD, Geschwind, DH & Hakonarson, H 2009, 'Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes', PLoS Genetics, vol. 5, no. 6, e1000536. https://doi.org/10.1371/journal.pgen.1000536
Bucan, Maja ; Abrahams, Brett S. ; Wang, Kai ; Glessner, Joseph T. ; Herman, Edward I. ; Sonnenblick, Lisa I. ; Alvarez Retuerto, Ana I. ; Imielinski, Marcin ; Hadley, Dexter ; Bradfield, Jonathan P. ; Kim, Cecilia ; Gidaya, Nicole B. ; Lindquist, Ingrid ; Hutman, Ted ; Sigman, Marian ; Kustanovich, Vlad ; Lajonchere, Clara M. ; Singleton, Andrew ; Kim, Junhyong ; Wassink, Thomas H. ; McMahon, William M. ; Owley, Thomas ; Sweeney, John A. ; Coon, Hilary ; Nurnberger, John I. ; Li, Mingyao ; Cantor, Rita M. ; Minshew, Nancy J. ; Sutcliffe, James S. ; Cook, Edwin H. ; Dawson, Geraldine ; Buxbaum, Joseph D. ; Grant, Struan F A ; Schellenberg, Gerard D. ; Geschwind, Daniel H. ; Hakonarson, Hakon. / Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes. In: PLoS Genetics. 2009 ; Vol. 5, No. 6.
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