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

ABSTRACT: 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.

SUBMITTER: Martin J

PROVIDER: S-EPMC5992329 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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

Martin Joanna J Walters Raymond K RK Demontis Ditte D Mattheisen Manuel M Lee S Hong SH Robinson Elise E Brikell Isabell I Ghirardi Laura L Larsson Henrik H Lichtenstein Paul P Eriksson Nicholas N Werge Thomas T Mortensen Preben Bo PB Pedersen Marianne Giørtz MG Mors Ole O Nordentoft Merete M Hougaard David M DM Bybjerg-Grauholm Jonas J Wray Naomi R NR Franke Barbara B Faraone Stephen V SV O'Donovan Michael C MC Thapar Anita A Børglum Anders D AD Neale Benjamin M BM

Biological psychiatry 20171202 12

<h4>Background</h4>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.<h4>Methods</h4>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 ...[more]

PMID: 29325848

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Project description:BackgroundAttention-deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder sharing genetic risk factors with other common psychiatric disorders. However, intergenerational recurrence patterns of ADHD from parents to sons and daughters are not known. We aimed to examine the risk of ADHD in offspring of parents with ADHD and parents with other psychiatric disorders by parental and offspring sex, using parents without the specific disorders as comparison.MethodsIn a generation study linking data from several population-based registries, all Norwegians born 1967-2011 (n = 2,486,088; Medical Birth Registry of Norway) and their parents were followed to 2015. To estimate intergenerational recurrence risk, we calculated prevalence differences (PD) and the relative risk (RR) of ADHD in offspring by parental ADHD, bipolar disorder (BD), schizophrenia spectrum disorder (SCZ), major depression (MDD), all by parental and offspring sex.ResultsThe absolute prevalence of ADHD in offspring of parents with ADHD was very high, especially in sons of two affected parents (41.5% and 25.1% in sons and daughters, respectively), and far higher than in offspring of parents with BD, SCZ or MDD. Intergenerational recurrence risks were higher for maternal than paternal ADHD (RRmaternal 8.4, 95% confidence interval (CI) 8.2-8.6 vs. RRpaternal 6.2, 6.0-6.4) and this was also true on the absolute scale (PDmaternal 21.1% (20.5-21.7) vs. PDpaternal 14.8% (14.3-15.4)). RRs were higher in daughters, while PDs higher in sons. Parental SCZ, BD and MDD were associated with an approximately doubled risk of offspring ADHD compared to parents without the respective disorders, and estimates did not differ significantly between daughters and sons.ConclusionsThe intergenerational recurrence risks of ADHD were high and higher from mothers with ADHD than fathers with ADHD. Other parental psychiatric disorders also conferred increased risk of offspring ADHD, but far lower, indicating a sex- and diagnosis-specific intergenerational recurrence risk in parents with ADHD.

Dataset Information

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

Publications

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

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