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Original Investigation
January 8, 2020

Shared Genetic Loci Between Body Mass Index and Major Psychiatric Disorders: A Genome-wide Association Study

Author Affiliations
  • 1NORMENT Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
  • 2Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
  • 3Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
  • 4Department of Radiology, University of California, San Diego, La Jolla
  • 5Department of Cognitive Science, University of California, San Diego, La Jolla
  • 6Multimodal Imaging Laboratory, University of California, San Diego, La Jolla
  • 7Department of Psychiatry, University of California, San Diego, La Jolla
  • 8Department of Neurosciences, University of California, San Diego, La Jolla
  • 9NORMENT Centre, Department of Clinical Science, University of Bergen, Bergen, Norway
JAMA Psychiatry. Published online January 8, 2020. doi:10.1001/jamapsychiatry.2019.4188
Key Points

Question  Are there genome-wide genetic factors underlying both body mass index and major psychiatric disorders?

Findings  In this study of combined genome-wide association data from 1 380 284 individuals, genetic overlap between body mass index and major psychiatric disorders (ie, schizophrenia, bipolar disorder, and major depression) was found.

Meaning  These findings identify common genetic loci body mass index and major psychiatric disorders and indicate mixed association directions with mainly opposite associations in schizophrenia and body mass index.

Abstract

Importance  People with major psychiatric disorders (MPDs) have a 10- to 20-year shorter life span than the rest of the population, and this difference is mainly due to comorbid cardiovascular diseases. Genome-wide association studies have identified common variants involved in schizophrenia (SCZ), bipolar disorder (BIP), and major depression (MD) and body mass index (BMI), a key cardiometabolic risk factor. However, genetic variants jointly influencing MPD and BMI remain largely unknown.

Objective  To assess the extent of the overlap between the genetic architectures of MPDs and BMI and identify genetic loci shared between them.

Design, Setting, and Participants  Using a conditional false discovery rate statistical framework, independent genome-wide association study data on individuals with SCZ (n = 82 315), BIP (n = 51 710), MD (n = 480 359), and BMI (n = 795 640) were analyzed. The UK Biobank cohort (n = 29 740) was excluded from the MD data set to avoid sample overlap. Data were collected from August 2017 to May 2018, and analysis began July 2018.

Main Outcomes and Measures  The primary outcomes were a list of genetic loci shared between BMI and MPDs and their functional pathways.

Results  Genome-wide association study data from 1 380 284 participants were analyzed, and the genetic correlation between BMI and MPDs varied (SCZ: r for genetic = −0.11, P = 2.1 × 10−10; BIP: r for genetic = −0.06, P = .0103; MD: r for genetic = 0.12, P = 6.7 × 10−10). Overall, 63, 17, and 32 loci shared between BMI and SCZ, BIP, and MD, respectively, were analyzed at conjunctional false discovery rate less than 0.01. Of the shared loci, 34% (73 of 213) in SCZ, 52% (36 of 69) in BIP, and 57% (56 of 99) in MD had risk alleles associated with higher BMI (conjunctional false discovery rate <0.05), while the rest had opposite directions of associations. Functional analyses indicated that the overlapping loci are involved in several pathways including neurodevelopment, neurotransmitter signaling, and intracellular processes, and the loci with concordant and opposite association directions pointed mostly to different pathways.

Conclusions and Relevance  In this genome-wide association study, extensive polygenic overlap between BMI and SCZ, BIP, and MD were found, and 111 shared genetic loci were identified, implicating novel functional mechanisms. There was mixture of association directions in SCZ and BMI, albeit with a preponderance of discordant ones.

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