Preben Bo Mortensen

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

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DOI

  • Jacob L Taylor, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, 02412, USA.
  • ,
  • Jean-Christophe P G Debost
  • Sarah U Morton, Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
  • ,
  • Emilie M Wigdor, Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
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  • Henrike O Heyne, Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
  • ,
  • Dennis Lal, 1] Institute for Molecular Medicine Finland (FIMM), University of Helsinki, FI-00014, Finland. [2] Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. [3] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA. [4] Psychiatric &Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
  • ,
  • Daniel P Howrigan, Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
  • ,
  • Alex Bloemendal, Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
  • ,
  • Janne T Larsen
  • Jack A Kosmicki, Program in Genetics and Genomics, Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, 02115, USA.
  • ,
  • Daniel J Weiner, Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
  • ,
  • Jason Homsy, Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA
  • ,
  • Jonathan G Seidman, Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA
  • ,
  • Christine E Seidman, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, 02115, USA.
  • ,
  • Esben Agerbo
  • John J McGrath
  • Preben Bo Mortensen
  • Liselotte Petersen
  • Mark J Daly, Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
  • ,
  • Elise B Robinson, Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA. erobinso@hsph.harvard.edu.

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.

OriginalsprogEngelsk
Artikelnummer3043
TidsskriftNature Communications
Vol/bind10
Nummer1
ISSN2041-1723
DOI
StatusUdgivet - 2019

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