TY - JOUR
T1 - Identification of ADHD risk genes in extended pedigrees by combining linkage analysis and whole-exome sequencing
AU - Corominas, Jordi
AU - Klein, Marieke
AU - Zayats, Tetyana
AU - Rivero, Olga
AU - Ziegler, Georg C.
AU - Pauper, Marc
AU - Neveling, Kornelia
AU - Poelmans, Geert
AU - Jansch, Charline
AU - Svirin, Evgeniy
AU - Geissler, Julia
AU - Weber, Heike
AU - Reif, Andreas
AU - Vasquez, Alejandro Arias
AU - Galesloot, Tessel E.
AU - Kiemeney, Lambertus A. L. M.
AU - Buitelaar, Jan K.
AU - Ramos-Quiroga, Josep-Antoni
AU - Cormand, Bru
AU - Ribases, Marta
AU - Hveem, Kristian
AU - Gabrielsen, Maiken Elvestad
AU - Hoffmann, Per
AU - Cichon, Sven
AU - Haavik, Jan
AU - Johansson, Stefan
AU - Jacob, Christian P.
AU - Romanos, Marcel
AU - Franke, Barbara
AU - Lesch, Klaus-Peter
N1 - Publisher Copyright:
© 2018, The Author(s).
PY - 2020/9
Y1 - 2020/9
N2 - 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 theAAED1gene reached significance. A rare variant (rs151326868) withinAAED1segregated 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.
AB - 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 theAAED1gene reached significance. A rare variant (rs151326868) withinAAED1segregated 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.
KW - DEFICIT HYPERACTIVITY DISORDER
KW - DE-NOVO MUTATIONS
KW - MOLECULAR-GENETICS
KW - ATTENTION
KW - ASSOCIATION
KW - VARIANTS
KW - AGE
KW - SUSCEPTIBILITY
KW - DUPLICATIONS
KW - METAANALYSIS
U2 - 10.1038/s41380-018-0210-6
DO - 10.1038/s41380-018-0210-6
M3 - Article
C2 - 30116028
SN - 1359-4184
VL - 25
SP - 2047
EP - 2057
JO - Molecular Psychiatry
JF - Molecular Psychiatry
IS - 9
ER -