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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 Genètica Attention deficit disorder with hyperactivity in adults Genetics |
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. |
Note: | Reproducció del document publicat a: https://doi.org/10.1038/s41380-018-0210-6 |
It is part of: | Molecular Psychiatry, 2018, vol. 25, p. 2047-2057 |
URI: | http://hdl.handle.net/2445/172103 |
Related resource: | https://doi.org/10.1038/s41380-018-0210-6 |
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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