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A Genetic Investigation of Sex Bias in the Prevalence of Attention-Deficit/Hyperactivity Disorder

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  • Joanna Martin
  • Raymond K Walters
  • Ditte Demontis
  • Manuel Mattheisen
  • S Hong Lee
  • Elise Robinson
  • Isabell Brikell
  • Laura Ghirardi
  • Henrik Larsson
  • Paul Lichtenstein
  • Nicholas Eriksson
  • Thomas Werge
  • Preben Bo Mortensen
  • Marianne Giørtz Pedersen
  • Ole Mors
  • Merete Nordentoft
  • David M Hougaard
  • Jonas Bybjerg-Grauholm
  • Naomi R Wray
  • Barbara Franke
  • Stephen V Faraone
  • Michael C O'Donovan
  • Anita Thapar
  • Anders D Børglum
  • Benjamin M Neale
  • 23andMe Research Team
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BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) shows substantial heritability and is two to seven times more common in male individuals than in female individuals. We examined two putative genetic mechanisms underlying this sex bias: sex-specific heterogeneity and higher burden of risk in female cases.

METHODS: We analyzed genome-wide autosomal common variants from the Psychiatric Genomics Consortium and iPSYCH Project (n = 20,183 cases, n = 35,191 controls) and Swedish population register data (n = 77,905 cases, n = 1,874,637 population controls).

RESULTS: Genetic correlation analyses using two methods suggested near complete sharing of common variant effects across sexes, with rg estimates close to 1. Analyses of population data, however, indicated that female individuals with ADHD may be at especially high risk for certain comorbid developmental conditions (i.e., autism spectrum disorder and congenital malformations), potentially indicating some clinical and etiological heterogeneity. Polygenic risk score analysis did not support a higher burden of ADHD common risk variants in female cases (odds ratio [confidence interval] = 1.02 [0.98-1.06], p = .28). In contrast, epidemiological sibling analyses revealed that the siblings of female individuals with ADHD are at higher familial risk for ADHD than the siblings of affected male individuals (odds ratio [confidence interval] = 1.14 [1.11-1.18], p = 1.5E-15).

CONCLUSIONS: Overall, this study supports a greater familial burden of risk in female individuals with ADHD and some clinical and etiological heterogeneity, based on epidemiological analyses. However, molecular genetic analyses suggest that autosomal common variants largely do not explain the sex bias in ADHD prevalence.

Original languageEnglish
JournalBiological Psychiatry
Issue number12
Pages (from-to)1044-1053
Publication statusPublished - 15 Jun 2018

    Research areas

  • Journal Article

ID: 52690522