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Identification of genetic overlap and novel risk loci for attention-deficit/hyperactivity disorder and bipolar disorder


Differential diagnosis between childhood onset attention-deficit/hyperactivity disorder (ADHD) and bipolar disorder (BD) remains a challenge, mainly due to overlapping symptoms and high rates of comorbidity. Despite this, genetic correlation reported for these disorders is low and non-significant. Here we aimed to better characterize the genetic architecture of these disorders utilizing recent large genome-wide association studies (GWAS). We analyzed independent GWAS summary statistics for ADHD (19,099 cases and 34,194 controls) and BD (20,352 cases and 31,358 controls) applying the conditional/conjunctional false discovery rate (condFDR/conjFDR) statistical framework that increases the power to detect novel phenotype-specific and shared loci by leveraging the combined power of two GWAS. We observed cross-trait polygenic enrichment for ADHD conditioned on associations with BD, and vice versa. Leveraging this enrichment, we identified 19 novel ADHD risk loci and 40 novel BD risk loci at condFDR <0.05. Further, we identified five loci jointly associated with ADHD and BD (conjFDR < 0.05). Interestingly, these five loci show concordant directions of effect for ADHD and BD. These results highlight a shared underlying genetic risk for ADHD and BD which may help to explain the high comorbidity rates and difficulties in differentiating between ADHD and BD in the clinic. Improving our understanding of the underlying genetic architecture of these disorders may aid in the development of novel stratification tools to help reduce these diagnostic difficulties.

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NIH (NS057198, EB00790); the Research Council of Norway (229129, 213837, 223273, 226971); the South-East Norway Regional Health Authority (2013-123); KG Jebsen Foundation (SKGJ-2011-36). The authors thank the Psychiatric Genetics Consortium (PGC) for access to GWAS data, and the many people who provided DNA samples. The authors thank Thomas Bjella, of the Oslo University Hospital & Institute of Clinical Medicine, for support with the database. The analyses were performed on resources provided by UNINETT Sigma2—the National Infrastructure for High Performance Computing and Data Storage in Norway.

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Correspondence to Kevin S. O’Connell or Ole A. Andreassen.

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Conflict of interest

Dr Andreassen has received a speaker’s honorarium from Lundbeck and a consultant for HealthLytix Inc. Dr. Dale reports that he is a Founder of and holds equity in CorTechs Labs, Inc., and serves on its Scientific Advisory Board. He is a member of the Scientific Advisory Board of Human Longevity, Inc. He receives funding through research grants from GE Healthcare to UCSD. The terms of these arrangements have been reviewed by and approved by UCSD in accordance with its conflict of interest policies. GBW, OOG, HS, and KS are employees of deCODE genetics/Amgen. The other authors have no conflicts of interest to declare.

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O’Connell, K.S., Shadrin, A., Bahrami, S. et al. Identification of genetic overlap and novel risk loci for attention-deficit/hyperactivity disorder and bipolar disorder. Mol Psychiatry 26, 4055–4065 (2021).

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