Contribution of autosomal rare and de novo variants to sex differences in autism

Autism Sequencing Consortium; Mahmoud Koko; F. Kyle Satterstrom

doi:10.1016/j.ajhg.2025.01.016

Contribution of autosomal rare and de novo variants to sex differences in autism

Autism Sequencing Consortium
, Mahmoud Koko
, F. Kyle Satterstrom

Research output: Contribution to journal › Article › Scientific › peer-review

4 Citations (Scopus)

Abstract

Autism is four times more prevalent in males than females. To study whether this reflects a difference in genetic predisposition attributed to autosomal rare variants, we evaluated sex differences in effect size of damaging protein-truncating and missense variants on autism predisposition in 47,061 autistic individuals using a liability model with differing thresholds. Given the sex differences in the rates of cognitive impairment among autistic individuals, we also compared effect sizes of rare variants between individuals with and without cognitive impairment or motor delay. Although these variants mediated different likelihoods of autism with versus without cognitive or motor difficulties, their effect sizes on the liability scale did not differ significantly by sex exome wide or in genes sex-differentially expressed in the cortex. De novo mutations were enriched in genes with male-biased expression in the adult cortex, but these genes did not show a significant sex difference on the liability scale, nor did the liability conferred by these genes differ significantly from other genes with similar loss-of-function intolerance and sex-averaged cortical expression. Exome-wide female bias in de novo protein-truncating mutation rates on the observed scale was driven by high-confidence and syndromic autism-predisposition genes. In summary, autosomal rare and damaging coding variants confer similar liability for autism in females and males.

Original language	English
Pages (from-to)	599-614
Number of pages	16
Journal	American Journal of Human Genetics
Volume	112
Issue number	3
DOIs	https://doi.org/10.1016/j.ajhg.2025.01.016
Publication status	Published - 6 Mar 2025
Externally published	Yes
Publication type	A1 Journal article-refereed

Funding

We thank the participants and investigators who contributed to the datasets of the Simons Foundation Powering Autism Research for Knowledge project, the Autism Sequencing Consortium (ASC), the Simons Simplex Collection, and the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) project. This work was supported by the Simons Foundation Autism Research Initiative (SFARI) through grant RNAG/669 G10 9280 to H.M., V.W., and other principal investigators of the Autism Prenatal Sex Differences Consortium (APEX). The ASC received support from SFARI ( 574598 , 736613 , and 647371 to S.J.S.; 575097 to B.D. and K.R.; 573206 to M.E.T. and M.J.D.; 571009 to J.D.; and 606362 and 608540 to M.E.T., M.J.D., J.D.B., B.D., K.R., and S.J.S., all from the consortia author list), NHGRI ( HG008895 to M.J.D., S.G., and M.E.T. from the consortia author list), NIMH ( MH115957 and MH123155 to M.E.T.; MH111658 and MH057881 to B.D.; MH097849 , MH111661 , and MH100233 to J.D.B.; MH109900 and MH123184 to K.R.; MH111660 and MH129722 to M.J.D.; and MH111662 and MH100027 to S.J.S., all from the consortia author list), NICHD ( HD081256 and HD096326 to M.E.T. from the consortia author list), AMED ( JP21WM0425007 to N.O. from the consortia author list), and the Beatrice and Samuel Seaver Foundation . We thank the participants and investigators who contributed to the datasets of the Simons Foundation Powering Autism Research for Knowledge (SPARK) project, the Autism Sequencing Consortium (ASC), the Simons Simplex Collection (SSC), and the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) project. This work was supported by the Simons Foundation Autism Research Initiative (SFARI) through grant RNAG/669 G10 9280 to H.M., V.W., and other principal investigators of the Autism Prenatal Sex Differences Consortium (APEX). The ASC received support from SFARI (574598, 736613, and 647371 to S.J.S.; 575097 to B.D. and K.R.; 573206 to M.E.T. and M.J.D.; 571009 to J.D.; and 606362 and 608540 to M.E.T., M.J.D., J.D.B., B.D., K.R., and S.J.S., all from the consortia author list), NHGRI (HG008895 to M.J.D., S.G., and M.E.T. from the consortia author list), NIMH (MH115957 and MH123155 to M.E.T.; MH111658 and MH057881 to B.D.; MH097849, MH111661, and MH100233 to J.D.B.; MH109900 and MH123184 to K.R.; MH111660 and MH129722 to M.J.D.; and MH111662 and MH100027 to S.J.S., all from the consortia author list), NICHD (HD081256 and HD096326 to M.E.T. from the consortia author list), AMED (JP21WM0425007 to N.O. from the consortia author list), and the Beatrice and Samuel Seaver Foundation. This research was funded in whole, or in part, by the Wellcome Trust (grant number 220540/Z/20/A). For the purpose of Open Access, the authors have applied a CC-BY public copyright licence to any Author Accepted Manuscript version from this submission.

Keywords

ASC
Autism Sequencing Consortium
exome sequencing
rare variant association
Simons Foundation Powering Autism Research for Knowledge
SPARK

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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10.1016/j.ajhg.2025.01.016Licence: CC BY

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@article{b9da2828d4684032b87a1a2eb52ff579,

title = "Contribution of autosomal rare and de novo variants to sex differences in autism",

abstract = "Autism is four times more prevalent in males than females. To study whether this reflects a difference in genetic predisposition attributed to autosomal rare variants, we evaluated sex differences in effect size of damaging protein-truncating and missense variants on autism predisposition in 47,061 autistic individuals using a liability model with differing thresholds. Given the sex differences in the rates of cognitive impairment among autistic individuals, we also compared effect sizes of rare variants between individuals with and without cognitive impairment or motor delay. Although these variants mediated different likelihoods of autism with versus without cognitive or motor difficulties, their effect sizes on the liability scale did not differ significantly by sex exome wide or in genes sex-differentially expressed in the cortex. De novo mutations were enriched in genes with male-biased expression in the adult cortex, but these genes did not show a significant sex difference on the liability scale, nor did the liability conferred by these genes differ significantly from other genes with similar loss-of-function intolerance and sex-averaged cortical expression. Exome-wide female bias in de novo protein-truncating mutation rates on the observed scale was driven by high-confidence and syndromic autism-predisposition genes. In summary, autosomal rare and damaging coding variants confer similar liability for autism in females and males.",

keywords = "ASC, Autism Sequencing Consortium, exome sequencing, rare variant association, Simons Foundation Powering Autism Research for Knowledge, SPARK",

author = "\{Autism Sequencing Consortium\} and Mahmoud Koko and Satterstrom, \{F. Kyle\} and Branko Aleksic and Mykyta Artomov and Mafalda Barbosa and Elisa Benetti and Catalina Betancur and Monica Biscaldi-Schafer and B{\o}rglum, \{Anders D.\} and Harrison Brand and Alfredo Brusco and Buxbaum, \{Joseph D.\} and Gabriele Campos and Simona Cardaropoli and Diana Carli and Angel Carracedo and Chan, \{Marcus C.Y.\} and Chiocchetti, \{Andreas G.\} and Chung, \{Brian H.Y.\} and Brett Collins and Collins, \{Ryan L.\} and Cook, \{Edwin H.\} and Hilary Coon and Costa, \{Claudia I.S.\} and Cuccaro, \{Michael L.\} and Cutler, \{David J.\} and Daly, \{Mark J.\} and \{De Rubeis\}, Silvia and Bernie Devlin and Doan, \{Ryan N.\} and Enrico Domenici and Shan Dong and Chiara Fallerini and Montserrat Fern{\'a}ndez-Prieto and Ferrero, \{Giovanni Battista\} and Freitag, \{Christine M.\} and Fu, \{Jack M.\} and Gargus, \{J. Jay\} and Sherif Gerges and Elisa Giorgio and Girardi, \{Ana Cristina\} and Stephen Guter and Emily Hansen-Kiss and Herman, \{Gail E.\} and Irva Hertz-Picciotto and Hougaard, \{David M.\} and Hultman, \{Christina M.\} and Miia Kaartinen and Terho Lehtim{\"a}ki and Kaija Puura",

note = "Publisher Copyright: {\textcopyright} 2025 The Authors",

year = "2025",

month = mar,

day = "6",

doi = "10.1016/j.ajhg.2025.01.016",

language = "English",

volume = "112",

pages = "599--614",

journal = "American Journal of Human Genetics",

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T1 - Contribution of autosomal rare and de novo variants to sex differences in autism

AU - Autism Sequencing Consortium

AU - Koko, Mahmoud

AU - Satterstrom, F. Kyle

AU - Aleksic, Branko

AU - Artomov, Mykyta

AU - Barbosa, Mafalda

AU - Benetti, Elisa

AU - Betancur, Catalina

AU - Biscaldi-Schafer, Monica

AU - Børglum, Anders D.

AU - Brand, Harrison

AU - Brusco, Alfredo

AU - Buxbaum, Joseph D.

AU - Campos, Gabriele

AU - Cardaropoli, Simona

AU - Carli, Diana

AU - Carracedo, Angel

AU - Chan, Marcus C.Y.

AU - Chiocchetti, Andreas G.

AU - Chung, Brian H.Y.

AU - Collins, Brett

AU - Collins, Ryan L.

AU - Cook, Edwin H.

AU - Coon, Hilary

AU - Costa, Claudia I.S.

AU - Cuccaro, Michael L.

AU - Cutler, David J.

AU - Daly, Mark J.

AU - De Rubeis, Silvia

AU - Devlin, Bernie

AU - Doan, Ryan N.

AU - Domenici, Enrico

AU - Dong, Shan

AU - Fallerini, Chiara

AU - Fernández-Prieto, Montserrat

AU - Ferrero, Giovanni Battista

AU - Freitag, Christine M.

AU - Fu, Jack M.

AU - Gargus, J. Jay

AU - Gerges, Sherif

AU - Giorgio, Elisa

AU - Girardi, Ana Cristina

AU - Guter, Stephen

AU - Hansen-Kiss, Emily

AU - Herman, Gail E.

AU - Hertz-Picciotto, Irva

AU - Hougaard, David M.

AU - Hultman, Christina M.

AU - Kaartinen, Miia

AU - Lehtimäki, Terho

AU - Puura, Kaija

PY - 2025/3/6

Y1 - 2025/3/6

N2 - Autism is four times more prevalent in males than females. To study whether this reflects a difference in genetic predisposition attributed to autosomal rare variants, we evaluated sex differences in effect size of damaging protein-truncating and missense variants on autism predisposition in 47,061 autistic individuals using a liability model with differing thresholds. Given the sex differences in the rates of cognitive impairment among autistic individuals, we also compared effect sizes of rare variants between individuals with and without cognitive impairment or motor delay. Although these variants mediated different likelihoods of autism with versus without cognitive or motor difficulties, their effect sizes on the liability scale did not differ significantly by sex exome wide or in genes sex-differentially expressed in the cortex. De novo mutations were enriched in genes with male-biased expression in the adult cortex, but these genes did not show a significant sex difference on the liability scale, nor did the liability conferred by these genes differ significantly from other genes with similar loss-of-function intolerance and sex-averaged cortical expression. Exome-wide female bias in de novo protein-truncating mutation rates on the observed scale was driven by high-confidence and syndromic autism-predisposition genes. In summary, autosomal rare and damaging coding variants confer similar liability for autism in females and males.

AB - Autism is four times more prevalent in males than females. To study whether this reflects a difference in genetic predisposition attributed to autosomal rare variants, we evaluated sex differences in effect size of damaging protein-truncating and missense variants on autism predisposition in 47,061 autistic individuals using a liability model with differing thresholds. Given the sex differences in the rates of cognitive impairment among autistic individuals, we also compared effect sizes of rare variants between individuals with and without cognitive impairment or motor delay. Although these variants mediated different likelihoods of autism with versus without cognitive or motor difficulties, their effect sizes on the liability scale did not differ significantly by sex exome wide or in genes sex-differentially expressed in the cortex. De novo mutations were enriched in genes with male-biased expression in the adult cortex, but these genes did not show a significant sex difference on the liability scale, nor did the liability conferred by these genes differ significantly from other genes with similar loss-of-function intolerance and sex-averaged cortical expression. Exome-wide female bias in de novo protein-truncating mutation rates on the observed scale was driven by high-confidence and syndromic autism-predisposition genes. In summary, autosomal rare and damaging coding variants confer similar liability for autism in females and males.

KW - ASC

KW - Autism Sequencing Consortium

KW - exome sequencing

KW - rare variant association

KW - Simons Foundation Powering Autism Research for Knowledge

KW - SPARK

UR - https://www.scopus.com/pages/publications/85218974505

U2 - 10.1016/j.ajhg.2025.01.016

DO - 10.1016/j.ajhg.2025.01.016

M3 - Article

C2 - 39954678

AN - SCOPUS:85218974505

SN - 0002-9297

VL - 112

SP - 599

EP - 614

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 3

ER -

Contribution of autosomal rare and de novo variants to sex differences in autism

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