Rare complete knockouts in humans: population distribution and significant role in autism spectrum disorders.
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Abstract | To characterize the role of rare complete human knockouts in autism spectrum disorders (ASDs), we identify genes with homozygous or compound heterozygous loss-of-function (LoF) variants (defined as nonsense and essential splice sites) from exome sequencing of 933 cases and 869 controls. We identify a 2-fold increase in complete knockouts of autosomal genes with low rates of LoF variation (≤ 5% frequency) in cases and estimate a 3% contribution to ASD risk by these events, confirming this observation in an independent set of 563 probands and 4,605 controls. Outside the pseudoautosomal regions on the X chromosome, we similarly observe a significant 1.5-fold increase in rare hemizygous knockouts in males, contributing to another 2% of ASDs in males. Taken together, these results provide compelling evidence that rare autosomal and X chromosome complete gene knockouts are important inherited risk factors for ASD. |
Year of Publication | 2013
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Journal | Neuron
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Volume | 77
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Issue | 2
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Pages | 235-42
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Date Published | 2013 Jan 23
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ISSN | 1097-4199
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URL | |
DOI | 10.1016/j.neuron.2012.12.029
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PubMed ID | 23352160
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PubMed Central ID | PMC3613849
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Links | |
Grant list | U24 MH081810 / MH / NIMH NIH HHS / United States
RC2 HL102923 / HL / NHLBI NIH HHS / United States
UC2 HL102926 / HL / NHLBI NIH HHS / United States
R01 MH089208 / MH / NIMH NIH HHS / United States
UC2 HL103010 / HL / NHLBI NIH HHS / United States
HL-103010 / HL / NHLBI NIH HHS / United States
R37 MH057881 / MH / NIMH NIH HHS / United States
U54 HG003067 / HG / NHGRI NIH HHS / United States
P50HD055751 / HD / NICHD NIH HHS / United States
RC2 HL102926 / HL / NHLBI NIH HHS / United States
R01 MH089004 / MH / NIMH NIH HHS / United States
R01 MH061009 / MH / NIMH NIH HHS / United States
U24MH068457 / MH / NIMH NIH HHS / United States
1U24MH081810 / MH / NIMH NIH HHS / United States
R01MH061009 / MH / NIMH NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
R01MH089175 / MH / NIMH NIH HHS / United States
R01 MH057881 / MH / NIMH NIH HHS / United States
HL-102924 / HL / NHLBI NIH HHS / United States
RC2 HL102924 / HL / NHLBI NIH HHS / United States
P50 HD055751 / HD / NICHD NIH HHS / United States
HL-102926 / HL / NHLBI NIH HHS / United States
R01 MH089025 / MH / NIMH NIH HHS / United States
R01MH089004 / MH / NIMH NIH HHS / United States
R01MH089208 / MH / NIMH NIH HHS / United States
R01 MH089175 / MH / NIMH NIH HHS / United States
U24 MH068457 / MH / NIMH NIH HHS / United States
R01MH057881 / MH / NIMH NIH HHS / United States
UC2 HL102923 / HL / NHLBI NIH HHS / United States
UC2 HL102924 / HL / NHLBI NIH HHS / United States
HL-102925 / HL / NHLBI NIH HHS / United States
RC2 HL103010 / HL / NHLBI NIH HHS / United States
HL-102923 / HL / NHLBI NIH HHS / United States
R01MH089025 / MH / NIMH NIH HHS / United States
R01MH089482 / MH / NIMH NIH HHS / United States
RC2 HL102925 / HL / NHLBI NIH HHS / United States
UC2 HL102925 / HL / NHLBI NIH HHS / United States
R01 MH089482 / MH / NIMH NIH HHS / United States
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