Mendelian Randomisation study of Body Composition and Depression in people of East Asian Ancestry highlights potential setting-specific causality

Jessica O’Loughlin, Francesco Casanova, Zammy Fairhurst-Hunter, Laura D Howe, Amanda M M Hughes, Jessica Tyrrell*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

6 Citations (Scopus)

Abstract

Background
Extensive evidence links higher body mass index (BMI) to higher odds of depression in people of European ancestry. However, our understanding of the relationship across different settings and ancestries is limited. Here, we test the relationship between body composition and depression in people of East Asian ancestry.

Methods
Multiple Mendelian randomisation (MR) methods were used to test the relationship between (a) BMI and (b) waist-hip ratio (WHR) with depression. Firstly, we performed two-sample MR using genetic summary statistics from a recent genome-wide association study (GWAS) of depression (with 15,771 cases and 178,777 controls) in people of East Asian ancestry. We selected 838 single nucleotide polymorphisms (SNPs) correlated with BMI and 263 SNPs correlated with WHR as genetic instrumental variables to estimate the causal effect of BMI and WHR on depression using the inverse-variance weighted (IVW) method. We repeated these analyses stratifying by home location status: China versus UK or USA. Secondly, we performed one-sample MR in the China Kadoorie Biobank (CKB) in 100,377 participants. This allowed us to test the relationship separately in (a) males and females and (b) urban and rural dwellers. We also examined (c) the linearity of the BMI-depression relationship.

Results
Both MR analyses provided evidence that higher BMI was associated with lower odds of depression. For example, a genetically-instrumented 1-SD higher BMI in the CKB was associated with lower odds of depressive symptoms [OR: 0.77, 95% CI: 0.63, 0.95]. There was evidence of differences according to place of residence. Using the IVW method, higher BMI was associated with lower odds of depression in people of East Asian ancestry living in China but there was no evidence for an association in people of East Asian ancestry living in the USA or UK. Furthermore, higher genetic BMI was associated with differential effects in urban and rural dwellers within China.

Conclusions
This study provides the first MR evidence for an inverse relationship between BMI and depression in people of East Asian ancestry. This contrasts with previous findings in European populations and therefore the public health response to obesity and depression is likely to need to differ based on sociocultural factors for example, ancestry and place of residence. This highlights the importance of setting-specific causality when using genetic causal inference approaches and data from diverse populations to test hypotheses. This is especially important when the relationship tested is not purely biological and may involve sociocultural factors.
Original languageEnglish
Article number37
Pages (from-to)1-14
JournalBMC Medicine
Volume21
Issue number1
DOIs
Publication statusPublished - 1 Feb 2023

Bibliographical note

Funding Information:
JO, FC and JT are supported by an Academy of Medical Sciences (AMS) Springboard award, which is supported by the AMS, the Wellcome Trust, GCRF, the Government Department of Business, Energy and Industrial strategy, the British Heart Foundation and Diabetes UK [SBF004\1079]. RMF is supported by a Wellcome Senior Research Fellowship [WT220390]. LDH is supported by a Career Development Award from the UK Medical Research Council (MR/M020894/1); The Medical Research Council (MRC) and the University of Bristol support the MRC Integrative Epidemiology Unit [MC_UU_00011/1] (AH, LDH). The CKB baseline survey and the first re-survey were supported by the Kadoorie Charitable Foundation in Hong Kong. Long-term follow-up was supported by the Wellcome Trust (212946/Z/18/Z, 202922/Z/16/Z, 104085/Z/14/Z, 088158/Z/09/Z), the National Key Research and Development Program of China (2016YFC0900500, 2016YFC0900501, 2016YFC0900504, 2016YFC1303904), and the National Natural Science Foundation of China (91843302). DNA extraction and genotyping was funded by GlaxoSmithKline and the UK Medical Research Council (MC-PC-13049, MC-PC-14135). The project is supported by core funding from the UK Medical Research Council (MC_UU_00017/1, MC_UU_12026/2, MC_U137686851), Cancer Research UK (C16077/A29186; C500/A16896), and the British Heart Foundation (CH/1996001/9454) to the Clinical Trial Service Unit and Epidemiological Studies Unit and to the MRC Population Health Research Unit at Oxford University. This research was funded in part, by the Wellcome Trust [WT220390]. For the purpose of open access, the authors have applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. This study was supported by the National Institute for Health and Care Research Exeter Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.

Publisher Copyright:
© 2023, The Author(s).

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