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Title: Identification of ADHD risk genes in extended pedigrees by combining linkage analysis and whole-exome sequencing
Author: Corominas, Jordi
Klein, Marieke
Zayats, Tetyana
Rivero, Olga
Ziegler, Georg C.
Pauper, Marc
Neveling, Kornelia
Poelmans, Geert
Jansch, Charline
Svirin, Evgeniy
Geissler, Julia
Weber, Heike
Reif, Andreas
Arias Vasquez, Alejandro
Galesloot, Tessel E.
Kiemeney, Lambertus A. L. M.
Buitelaar, Jan K.
Ramos Quiroga, Josep Antoni
Cormand Rifà, Bru
Ribasés Haro, Marta
Hveem, Kristian
Gabrielsen, Maiken Elvestad
Hoffmann, Per
Jacob, Christian P.
Romanos, Marcel
Franke, Barbara
Lesch, Klaus-Peter
Keywords: Trastorns per dèficit d'atenció amb hiperactivitat en els adults
Attention deficit disorder with hyperactivity in adults
Issue Date: 16-Aug-2018
Publisher: Nature Publishing Group
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 (Ntotal = 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.
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It is part of: Molecular Psychiatry, 2018, vol. 25, p. 2047-2057
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ISSN: 1359-4184
Appears in Collections:Articles publicats en revistes (Genètica, Microbiologia i Estadística)
Articles publicats en revistes (Institut de Biomedicina (IBUB))

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