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Nat Commun. 2019 Jul 10;10(1):3043. doi: 10.1038/s41467-019-11039-6.

Paternal-age-related de novo mutations and risk for five disorders.

Taylor JL1,2,3, Debost JPG4,5,6, Morton SU7, Wigdor EM2,3,8, Heyne HO2,3,8, Lal D2,8,9,10, Howrigan DP2,8, Bloemendal A2,3,8, Larsen JT4,5, Kosmicki JA2,3,8,11, Weiner DJ2,3,8, Homsy J12, Seidman JG12, Seidman CE12,13,14, Agerbo E4,5,15, McGrath JJ4,16,17, Mortensen PB4,5,15,18, Petersen L4,5, Daly MJ2,3,8, Robinson EB19,20,21,22.

Author information

1
Department of Psychiatry, Brigham and Woman's Hospital, Boston, MA, 02115, USA.
2
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
3
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, 02412, USA.
4
National Centre for Register-based Research, Department of Economics and Business, Aarhus University, Aarhus, 8210, Denmark.
5
The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, 8210, Denmark.
6
Aarhus University Hospital, Risskov, Department P, Aarhus, 8200, Denmark.
7
Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
8
Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
9
Cologne Center for Genomics, University of Cologne, Cologne, 50923, Germany.
10
Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, 02114, USA.
11
Program in Genetics and Genomics, Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, 02115, USA.
12
Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA.
13
Cardiovascular Division, Brigham and Women's Hospital, Boston, MA, 02115, USA.
14
Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, 02115, USA.
15
Centre for Integrated Register-based Research, CIRRAU, Aarhus University, Aarhus, 8210, Denmark.
16
Queensland Brain Institute, The University of Queensland, Brisbane, 4072, Queensland, Australia.
17
Queensland Centre for Mental Health Research, The Park Centre for Mental Health, Richlands, 4076, Queensland, Australia.
18
Department of Biomedicine and iSEQ, Centre for Integrative Sequencing, Aarhus University, Aarhus, 08210, Denmark.
19
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. erobinso@hsph.harvard.edu.
20
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, 02412, USA. erobinso@hsph.harvard.edu.
21
Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA. erobinso@hsph.harvard.edu.
22
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA. erobinso@hsph.harvard.edu.

Abstract

There are established associations between advanced paternal age and offspring risk for psychiatric and developmental disorders. These are commonly attributed to genetic mutations, especially de novo single nucleotide variants (dnSNVs), that accumulate with increasing paternal age. However, the actual magnitude of risk from such mutations in the male germline is unknown. Quantifying this risk would clarify the clinical significance of delayed paternity. Using parent-child trio whole-exome-sequencing data, we estimate the relationship between paternal-age-related dnSNVs and risk for five disorders: autism spectrum disorder (ASD), congenital heart disease, neurodevelopmental disorders with epilepsy, intellectual disability and schizophrenia (SCZ). Using Danish registry data, we investigate whether epidemiologic associations between each disorder and older fatherhood are consistent with the estimated role of dnSNVs. We find that paternal-age-related dnSNVs confer a small amount of risk for these disorders. For ASD and SCZ, epidemiologic associations with delayed paternity reflect factors that may not increase with age.

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