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Identification of ADHD risk genes in extended pedigrees by combining linkage analysis and whole-exome sequencing.

ABSTRACT: Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder with a complex genetic background, hampering identification of underlying genetic risk factors. We hypothesized that combining linkage analysis and whole-exome sequencing (WES) in multi-generation pedigrees with multiple affected individuals can point toward novel ADHD genes. Three families with multiple ADHD-affected members (N_total?=?70) and apparent dominant inheritance pattern were included in this study. Genotyping was performed in 37 family members, and WES was additionally carried out in 10 of those. Linkage analysis was performed using multi-point analysis in Superlink Online SNP 1.1. From prioritized linkage regions with a LOD score???2, a total of 24 genes harboring rare variants were selected. Those genes were taken forward and were jointly analyzed in gene-set analyses of exome-chip data using the MAGMA software in an independent sample of patients with persistent ADHD and healthy controls (N?=?9365). The gene-set including all 24 genes together, and particularly the gene-set from one of the three families (12 genes), were significantly associated with persistent ADHD in this sample. Among the latter, gene-wide analysis for the AAED1 gene reached significance. A rare variant (rs151326868) within AAED1 segregated with ADHD in one of the families. The analytic strategy followed here is an effective approach for identifying novel ADHD risk genes. Additionally, this study suggests that both rare and more frequent variants in multiple genes act together in contributing to ADHD risk, even in individual multi-case families.

SUBMITTER: Corominas J

PROVIDER: S-EPMC7473839 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Identification of ADHD risk genes in extended pedigrees by combining linkage analysis and whole-exome sequencing.

Corominas Jordi J Klein Marieke M Zayats Tetyana T Rivero Olga O Ziegler Georg C GC Pauper Marc M Neveling Kornelia K Poelmans Geert G Jansch Charline C Svirin Evgeniy E Geissler Julia J Weber Heike H Reif Andreas A Arias Vasquez Alejandro A Galesloot Tessel E TE Kiemeney Lambertus A L M LALM Buitelaar Jan K JK Ramos-Quiroga Josep-Antoni JA Cormand Bru B Ribasés Marta M Hveem Kristian K Gabrielsen Maiken Elvestad ME Hoffmann Per P Cichon Sven S Haavik Jan J Johansson Stefan S Jacob Christian P CP Romanos Marcel M Franke Barbara B Lesch Klaus-Peter KP

Molecular psychiatry 20180816 9

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder with a complex genetic background, hampering identification of underlying genetic risk factors. We hypothesized that combining linkage analysis and whole-exome sequencing (WES) in multi-generation pedigrees with multiple affected individuals can point toward novel ADHD genes. Three families with multiple ADHD-affected members (N<sub>total</sub> = 70) and apparent dominant inheritance pattern were included in ...[more]

PMID: 30116028

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Project description:BACKGROUND:Family studies have shown a strong heritability component for venous thromboembolism (VTE), but established genetic risk factors are present in only half of VTE patients. AIM:To identify genetic risk factors in two large families with unexplained hereditary VTE. METHODS:We performed whole exome sequencing in 10 affected relatives of two unrelated families with an unexplained tendency for VTE. We prioritized variants shared by all affected relatives from both families, and evaluated these in the remaining affected and unaffected individuals. We prioritized variants based on 3 different filter strategies: variants within candidate genes, rare variants across the exome, and SNPs present in patients with familial VTE and with low frequency in the general population. We used whole exome sequencing data available from 96 unrelated VTE cases with a positive family history of VTE from an affected sib study (the GIFT study) to identify additional carriers and compared the risk-allele frequencies with the general population. Variants found in only one individual were also retained for further analysis. Finally, we assessed the association of these variants with VTE in a population-based case-control study (the MEGA study) with 4,291 cases and 4,866 controls. RESULTS:Six variants remained as putative disease-risk candidates. These variants are located in 6 genes spread among 3 different loci: 2p21 (PLEKHH2 NM_172069:c.3105T>C, LRPPRC rs372371276, SRBD1 rs34959371), 5q35.2 (UNC5A NM_133369.2:c.1869+23C>A), and 17q25.1 (GPRC5C rs142232982, RAB37 rs556450784). In GIFT, additional carriers were identified only for the variants located in the 2p21 locus. In MEGA, additional carriers for several of these variants were identified in both cases and controls, without a difference in prevalence; no carrier of the UNC5A variant was present. CONCLUSION:Despite sequencing of several individuals from two thrombophilic families resulting in 6 candidate variants, we were unable to confirm their relevance as novel thrombophilic defects.

Dataset Information

Identification of ADHD risk genes in extended pedigrees by combining linkage analysis and whole-exome sequencing.

Publications

Identification of ADHD risk genes in extended pedigrees by combining linkage analysis and whole-exome sequencing.

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