title: Paternal age at childbearing and offspring psychiatric and academic morbidity.
abstract: OBJECTIVE
  Advancing paternal age is associated with increased genetic mutations during spermatogenesis, which research suggests may cause psychiatric morbidity in the offspring. The effects of advancing paternal age at childbearing on offspring morbidity remain unclear, however, because of inconsistent epidemiologic findings and the inability of previous studies to rigorously rule out confounding factors.
  
  
  OBJECTIVE
  To examine the associations between advancing paternal age at childbearing and numerous indexes of offspring morbidity.
  
  
  METHODS
  We performed a population-based cohort study of all individuals born in Sweden in 1973-2001 (N = 2,615,081), with subsets of the data used to predict childhood or adolescent morbidity. We estimated the risk of psychiatric and academic morbidity associated with advancing paternal age using several quasi-experimental designs, including the comparison of differentially exposed siblings, cousins, and first-born cousins.
  
  
  METHODS
  Paternal age at childbearing.
  
  
  METHODS
  Psychiatric (autism, attention-deficit/hyperactivity disorder, psychosis, bipolar disorder, suicide attempt, and substance use problem) and academic (failing grades and low educational attainment) morbidity.
  
  
  RESULTS
  In the study population, advancing paternal age was associated with increased risk of some psychiatric disorders (eg, autism, psychosis, and bipolar disorders) but decreased risk of the other indexes of morbidity. In contrast, the sibling-comparison analyses indicated that advancing paternal age had a dose-response relationship with every index of morbidity, with the magnitude of the associations being as large or larger than the estimates in the entire population. Compared with offspring born to fathers 20 to 24 years old, offspring of fathers 45 years and older were at heightened risk of autism (hazard ratio [HR] = 3.45; 95% CI, 1.62-7.33), attention-deficit/hyperactivity disorder (HR = 13.13; 95% CI, 6.85-25.16), psychosis (HR = 2.07; 95% CI, 1.35-3.20), bipolar disorder (HR = 24.70; 95% CI, 12.12-50.31), suicide attempts (HR = 2.72; 95% CI, 2.08-3.56), substance use problems (HR = 2.44; 95% CI, 1.98-2.99), failing a grade (odds ratio [OR] = 1.59; 95% CI, 1.37-1.85), and low educational attainment (OR = 1.70; 95% CI, 1.50-1.93) in within-sibling comparisons. Additional analyses using several quasi-experimental designs obtained commensurate results, further strengthening the internal and external validity of the findings.
  
  
  CONCLUSIONS
  Advancing paternal age is associated with increased risk of psychiatric and academic morbidity, with the magnitude of the risks being as large or larger than previous estimates. These findings are consistent with the hypothesis that new genetic mutations that occur during spermatogenesis are causally related to offspring morbidity.
authors.affiliation: Department of Psychological and Brain Sciences, Indiana University, Bloomington.
authors.forename: Brian M
authors.initials: BM
authors.lastname: D'Onofrio
authors.affiliation: Department of Psychological and Brain Sciences, Indiana University, Bloomington.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Rickert
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Emma
authors.initials: E
authors.lastname: Frans
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ralf
authors.initials: R
authors.lastname: Kuja-Halkola
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden3Lung and Allergy Unit, Astrid Lindgren Children's Hospital, Stockholm, Sweden.
authors.forename: Catarina
authors.initials: C
authors.lastname: Almqvist
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Arvid
authors.initials: A
authors.lastname: Sjölander
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Henrik
authors.initials: H
authors.lastname: Larsson
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Paul
authors.initials: P
authors.lastname: Lichtenstein
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D004522:Educational Status; D005260:Female; D006801:Humans; D007859:Learning Disabilities / Q000175:diagnosis* / Q000453:epidemiology* / Q000235:genetics / Q000523:psychology; D008297:Male; D001523:Mental Disorders / Q000175:diagnosis* / Q000453:epidemiology* / Q000235:genetics / Q000523:psychology; D008875:Middle Aged; D010331:Paternal Age; D012307:Risk Factors; D013223:Statistics as Topic; D013548:Sweden; D055815:Young Adult