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Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains.

ABSTRACT: Attention-deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder with a major genetic component. Here, we present a genome-wide association study meta-analysis of ADHD comprising 38,691 individuals with ADHD and 186,843 controls. We identified 27 genome-wide significant loci, highlighting 76 potential risk genes enriched among genes expressed particularly in early brain development. Overall, ADHD genetic risk was associated with several brain-specific neuronal subtypes and midbrain dopaminergic neurons. In exome-sequencing data from 17,896 individuals, we identified an increased load of rare protein-truncating variants in ADHD for a set of risk genes enriched with probable causal common variants, potentially implicating SORCS3 in ADHD by both common and rare variants. Bivariate Gaussian mixture modeling estimated that 84-98% of ADHD-influencing variants are shared with other psychiatric disorders. In addition, common-variant ADHD risk was associated with impaired complex cognition such as verbal reasoning and a range of executive functions, including attention.

SUBMITTER: Demontis D

PROVIDER: S-EPMC10914347 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains.

Demontis Ditte D Walters G Bragi GB Athanasiadis Georgios G Walters Raymond R Therrien Karen K Nielsen Trine Tollerup TT Farajzadeh Leila L Voloudakis Georgios G Bendl Jaroslav J Zeng Biau B Zhang Wen W Grove Jakob J Als Thomas D TD Duan Jinjie J Satterstrom F Kyle FK Bybjerg-Grauholm Jonas J Bækved-Hansen Marie M Gudmundsson Olafur O OO Magnusson Sigurdur H SH Baldursson Gisli G Davidsdottir Katrin K Haraldsdottir Gyda S GS Agerbo Esben E Hoffman Gabriel E GE Dalsgaard Søren S Martin Joanna J Ribasés Marta M Boomsma Dorret I DI Soler Artigas Maria M Roth Mota Nina N Howrigan Daniel D Medland Sarah E SE Zayats Tetyana T Rajagopal Veera M VM Nordentoft Merete M Mors Ole O Hougaard David M DM Mortensen Preben Bo PB Daly Mark J MJ Faraone Stephen V SV Stefansson Hreinn H Roussos Panos P Franke Barbara B Werge Thomas T Neale Benjamin M BM Stefansson Kari K Børglum Anders D AD

Nature genetics 20230126 2

Attention-deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder with a major genetic component. Here, we present a genome-wide association study meta-analysis of ADHD comprising 38,691 individuals with ADHD and 186,843 controls. We identified 27 genome-wide significant loci, highlighting 76 potential risk genes enriched among genes expressed particularly in early brain development. Overall, ADHD genetic risk was associated with several brain-specific neuronal subtypes ...[more]

PMID: 36702997

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Project description:Alcohol consumption is a known risk factor for hypertension, with recent candidate studies implicating gene-alcohol interactions in blood pressure (BP) regulation. We used 6882 (predominantly) Caucasian participants aged 20-80 years from the Framingham SNP Health Association Resource (SHARe) to perform a genome-wide analysis of SNP-alcohol interactions on BP traits. We used a two-step approach in the ABEL suite to examine genetic interactions with three alcohol measures (ounces of alcohol consumed per week, drinks consumed per week, and the number of days drinking alcohol per week) on four BP traits [systolic (SBP), diastolic (DBP), mean arterial (MAP), and pulse (PP) pressure]. In the first step, we fit a linear mixed model of each BP trait onto age, sex, BMI, and antihypertensive medication while accounting for the phenotypic correlation among relatives. In the second step, we conducted 1 degree-of-freedom (df) score tests of the SNP main effect, alcohol main effect, and SNP-alcohol interaction using the maximum likelihood estimates (MLE) of the parameters from the first step. We then calculated the joint 2 df score test of the SNP main effect and SNP-alcohol interaction using MixABEL. The effect of SNP rs10826334 (near SLC16A9) on SBP was significantly modulated by both the number of alcoholic drinks and the ounces of alcohol consumed per week (p-values of 1.27E-08 and 3.92E-08, respectively). Each copy of the G-allele decreased SBP by 3.79 mmHg in those consuming 14 drinks per week vs. a 0.461 mmHg decrease in non-drinkers. Index SNPs in 20 other loci exhibited suggestive (p-value ≤ 1E-06) associations with BP traits by the 1 df interaction test or joint 2 df test, including 3 rare variants, one low-frequency variant, and SNPs near/in genes ESRRG, FAM179A, CRIPT-SOCS5, KAT2B, ADCY2, GLI3, ZNF716, SLIT1, PDE3A, KERA-LUM, RNF219-AS1, CLEC3A, FBXO15, and IGSF5. SNP-alcohol interactions may enhance discovery of novel variants with large effects that can be targeted with lifestyle modifications.

Dataset Information

Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains.

Publications

Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains.

Similar Datasets

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