Rare complete knockouts in humans: population distribution and significant role in autism spectrum disorders.
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.
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
Elaine T
ET
Lim
Soumya
S
Raychaudhuri
Stephan J
SJ
Sanders
Christine
C
Stevens
Aniko
A
Sabo
Daniel G
DG
MacArthur
Benjamin M
BM
Neale
Andrew
A
Kirby
Douglas M
DM
Ruderfer
Menachem
M
Fromer
Monkol
M
Lek
Li
L
Liu
Jason
J
Flannick
Stephan
S
Ripke
Uma
U
Nagaswamy
Donna
D
Muzny
Jeffrey G
JG
Reid
Alicia
A
Hawes
Irene
I
Newsham
Yuanqing
Y
Wu
Lora
L
Lewis
Huyen
H
Dinh
Shannon
S
Gross
Li-San
LS
Wang
Chiao-Feng
CF
Lin
Otto
O
Valladares
Stacey B
SB
Gabriel
Mark
M
dePristo
David M
DM
Altshuler
Shaun M
SM
Purcell
Matthew W
MW
State
Eric
E
Boerwinkle
Joseph D
JD
Buxbaum
Edwin H
EH
Cook
Richard A
RA
Gibbs
Gerard D
GD
Schellenberg
James S
JS
Sutcliffe
Bernie
B
Devlin
Kathryn
K
Roeder
Mark J
MJ
Daly
D016022:Case-Control Studies; D002659:Child Development Disorders, Pervasive / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics*; D002675:Child, Preschool; D041321:Chromosomes, Human, X / Q000235:genetics; D003710:Demography / Q000379:methods*; D005260:Female; D017353:Gene Deletion; D014644:Genetic Variation / Q000235:genetics; D006720:Homozygote; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D019656:Loss of Heterozygosity / Q000235:genetics*; D008297:Male; D012307:Risk Factors