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

Jacob L. Taylor, Jean-Christophe P. G. Debost, Sarah U. Morton, Emilie M. Wigdor, Henrike O. Heyne, Dennis Lal, Daniel P. Howrigan, Alex Bloemendal, Janne T. Larsen, Jack A. Kosmicki, Daniel J. Weiner, Jason Homsy, Jonathan G. Seidman, Christine E. Seidman, Esben Agerbo, John J. McGrath, Preben Bo Mortensen, Liselotte Petersen, Mark J. Daly and Elise B. Robinson ()
Additional contact information
Jacob L. Taylor: Brigham and Woman’s Hospital
Jean-Christophe P. G. Debost: Department of Economics and Business, Aarhus University
Sarah U. Morton: Boston Children’s Hospital and Harvard Medical School
Emilie M. Wigdor: Broad Institute of MIT and Harvard
Henrike O. Heyne: Broad Institute of MIT and Harvard
Dennis Lal: Broad Institute of MIT and Harvard
Daniel P. Howrigan: Broad Institute of MIT and Harvard
Alex Bloemendal: Broad Institute of MIT and Harvard
Janne T. Larsen: Department of Economics and Business, Aarhus University
Jack A. Kosmicki: Broad Institute of MIT and Harvard
Daniel J. Weiner: Broad Institute of MIT and Harvard
Jason Homsy: Harvard Medical School
Jonathan G. Seidman: Harvard Medical School
Christine E. Seidman: Harvard Medical School
Esben Agerbo: Department of Economics and Business, Aarhus University
John J. McGrath: Department of Economics and Business, Aarhus University
Preben Bo Mortensen: Department of Economics and Business, Aarhus University
Liselotte Petersen: Department of Economics and Business, Aarhus University
Mark J. Daly: Broad Institute of MIT and Harvard
Elise B. Robinson: Broad Institute of MIT and Harvard

Nature Communications, 2019, vol. 10, issue 1, 1-9

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11039-6

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