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

Jordi Corominas, Marieke Klein, Tetyana Zayats, Olga Rivero, Georg C. Ziegler, Marc Pauper, Kornelia Neveling, Geert Poelmans, Charline Jansch, Evgeniy Svirin, Julia Geissler, Heike Weber, Andreas Reif, Alejandro Arias Vasquez, Tessel E. Galesloot, Lambertus A. L. M. Kiemeney, Jan K. Buitelaar, Josep-Antoni Ramos-Quiroga, Bru Cormand, Marta RibasesKristian Hveem, Maiken Elvestad Gabrielsen, Per Hoffmann, Sven Cichon, Jan Haavik, Stefan Johansson, Christian P. Jacob, Marcel Romanos, Barbara Franke*, Klaus-Peter Lesch*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

16 Citations (Web of Science)


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.

Original languageEnglish
Pages (from-to)2047-2057
Number of pages11
JournalMolecular Psychiatry
Issue number9
Publication statusPublished - Sept 2020


  • AGE

Cite this