Identification of shared and differentiating genetic architecture for autism spectrum disorder, attention-deficit hyperactivity disorder and case subgroups

被引：39

作者：

Mattheisen, Manuel ^{[1
,2
,3
,4
,5
]}

Grove, Jakob ^{[1
,2
,6
,7
,8
]}

Als, Thomas D. ^{[1
,2
,6
,7
]}

Martin, Joanna ^{[9
]}

Voloudakis, Georgios ^{[10
,11
,12
]}

Meier, Sandra ^{[1
,2
,3
,4
]}

Demontis, Ditte ^{[1
,2
,6
,7
]}

Bendl, Jaroslav ^{[10
,11
,12
]}

Walters, Raymond ^{[13
,14
]}

Carey, Caitlin E. ^{[13
,14
]}

Rosengren, Anders ^{[6
,15
]}

Strom, Nora, I ^{[1
,2
,5
,16
]}

Hauberg, Mads Engel ^{[10
,11
,12
]}

Zeng, Biao ^{[10
,11
,12
]}

Hoffman, Gabriel ^{[10
,11
,12
]}

Zhang, Wen ^{[10
,11
,12
]}

Bybjerg-Grauholm, Jonas ^{[6
,17
]}

Baekvad-Hansen, Marie ^{[6
,17
]}

Agerbo, Esben ^{[6
,18
,19
]}

Cormand, Bru ^{[20
,21
,22
,23
]}

Nordentoft, Merete ^{[6
,24
,25
,26
]}

Werge, Thomas ^{[6
,15
,24
,27
]}

Mors, Ole ^{[6
,28
]}

Hougaard, David M. ^{[6
,17
]}

Buxbaum, Joseph D. ^{[12
,29
,30
,31
]}

Faraone, Stephen, V ^{[32
,33
]}

Franke, Barbara ^{[34
,35
]}

Dalsgaard, Soren ^{[18
]}

Mortensen, Preben B. ^{[6
,7
,18
,19
]}

Robinson, Elise B. ^{[13
,14
,36
]}

Roussos, Panos ^{[10
,11
,12
,31
,37
]}

Neale, Benjamin M. ^{[13
,14
]}

Daly, Mark J. ^{[13
,14
,38
,39
]}

Borglum, Anders D. ^{[1
,2
,6
,7
]}

机构：

[1] Aarhus Univ, Dept Biomed Human Genet, Aarhus, Denmark

[2] Aarhus Univ, iSEQ Ctr, Aarhus, Denmark

[3] Dalhousie Univ, Dept Community Hlth & Epidemiol, Halifax, NS, Canada

[4] Dalhousie Univ, Dept Psychiat, Halifax, NS, Canada

[5] Ludwig Maximilians Univ Munchen, Inst Psychiat Phen & Genom IPPG, Univ Hosp, Munich, Germany

[6] iPSYCH, Lundbeck Fdn Initiat Integrat Psychiat Res, Aarhus, Denmark

[7] Ctr Genom & Personalized Med, Aarhus, Denmark

[8] Aarhus Univ, Bioinformat Res Ctr, Aarhus, Denmark

[9] Cardiff Univ, MRC Ctr Neuropsychiat Genet & Genom, Cardiff, Wales

[10] Icahn Sch Med Mt Sinai, Ctr Dis Neurogen, New York, NY 10029 USA

[11] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, Icahn Inst Data Sci & Genom Technol, New York, NY 10029 USA

[12] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA

[13] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02115 USA

[14] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA

[15] Copenhagen Univ Hosp, Inst Biol Psychiat, Mental Hlth Serv Copenhagen, Copenhagen, Denmark

[16] Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, Stockholm, Sweden

[17] Statens Serum Inst, Ctr Neonatal Screening, Dept Congenital Disorders, Copenhagen, Denmark

[18] Aarhus Univ, Natl Ctr Register Based Res, Aarhus, Denmark

[19] Aarhus Univ, Ctr Integrated Register Based Res, Aarhus, Denmark

[20] Univ Barcelona, Fac Biol, Dept Genet Microbiol & Stat, Barcelona, Catalonia, Spain

[21] Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid, Spain

[22] Univ Barcelona IBUB, Inst Biomed, Barcelona, Catalonia, Spain

[23] Inst Recerca St Joan de Deu IR SJD, Esplugas de Llobregat, Catalonia, Spain

[24] Univ Copenhagen, Fac Hlth Sci, Dept Clin Med, Copenhagen, Denmark

[25] Copenhagen Res Ctr Mental Hlth CORE, Mental Hlth Ctr Copenhagen, Copenhagen, Denmark

[26] Univ Hosp, Hellerup, Denmark

[27] Univ Copenhagen, Ctr GeoGenet, GLOBE Inst, Copenhagen, Denmark

[28] Aarhus Univ Hosp Psychiat, Psychosis Res Unit, Aarhus, Denmark

[29] Icahn Sch Med Mt Sinai, Seaver Autism Ctr Res & Treatment, New York, NY 10029 USA

[30] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA

[31] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA

[32] SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY 13210 USA

[33] SUNY Upstate Med Univ, Dept Neurosci & Physiol, Syracuse, NY 13210 USA

[34] Radboud Univ Nijmegen Med Ctr, Donders Inst Brain Cognit & Behav, Dept Psychiat, Nijmegen, Netherlands

[35] Radboud Univ Nijmegen Med Ctr, Donders Inst Brain Cognit & Behav, Dept Human Genet, Nijmegen, Netherlands

[36] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA

[37] JJ Peters VA Med Ctr, Dept Psychiat, Bronx, NY USA

[38] Harvard Med Sch, Dept Med, Boston, MA 02115 USA

[39] Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland

来源：

NATURE GENETICS | 2022年 / 54卷 / 10期

基金：

欧盟地平线“2020”;

关键词：

GENOME-WIDE ASSOCIATION; LD SCORE REGRESSION; DEFICIT/HYPERACTIVITY DISORDER; PSYCHIATRIC-DISORDERS; CHILDREN; METAANALYSIS; LOCI; HERITABILITY; RISK; ADHD;

D O I：

10.1038/s41588-022-01171-3

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Cross-disorder genetic association analyses identify five loci differentiating attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Individuals diagnosed with both ADHD and ASD are double-loaded with genetic risk for both disorders. Attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are highly heritable neurodevelopmental conditions, with considerable overlap in their genetic etiology. We dissected their shared and distinct genetic etiology by cross-disorder analyses of large datasets. We identified seven loci shared by the disorders and five loci differentiating them. All five differentiating loci showed opposite allelic directions in the two disorders and significant associations with other traits, including educational attainment, neuroticism and regional brain volume. Integration with brain transcriptome data enabled us to identify and prioritize several significantly associated genes. The shared genomic fraction contributing to both disorders was strongly correlated with other psychiatric phenotypes, whereas the differentiating portion was correlated most strongly with cognitive traits. Additional analyses revealed that individuals diagnosed with both ASD and ADHD were double-loaded with genetic predispositions for both disorders and showed distinctive patterns of genetic association with other traits compared with the ASD-only and ADHD-only subgroups. These results provide insights into the biological foundation of the development of one or both conditions and of the factors driving psychopathology discriminatively toward either ADHD or ASD.

引用

页码：1470 / +

页数：15

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