Mendelian randomisation study of body composition and depression in people of East Asian ancestry highlights potential setting-specific causality

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.

The causal role of adiposity in mental illness: A systematic review and meta-analysis of Mendelian randomization studies

“…Twenty-eight studies reported 98 estimates of the association between adiposity and depression 25,32–35,37,40,42–45,47,48,50,53,55–59,62–64,66–70 , three studies reported 9 estimates for anxiety 25,41,67 , three studies reported 8 estimates for anorexia nervosa 61,67,68 , five studies reported 13 estimates for bipolar disorder 31,53,55,65,67 , three studies reported 7 estimates for OCD 61,67,68 , three studies reported 23 estimates for PTSD 49,60,67 , and twelve studies reported 26 estimates for schizophrenia 36,38,39,46,51,52,54,55,61,65,67,68 . One-sample MR design was conducted in six studies 33,34,43,56,57,62 , two-sample MR design was conducted in thirty-two studies 31,32,35–42,44–55,58,60,61,63–69 , both one-sample MR and two-sample MR were conducted in three studies 25,59,70 . Thirty unique MR estimates out of 184 total estimates were included in meta-analyses (details as shown in “Yes” under “For meta-analysis” collum in Appendix).…”

“…For the assessment of exposure and outcome, 86% of studies used adiposity data from the UK Biobank and mental illness data from Psychiatric Genomics Consortium. For the selection of genetic variants, most studies selected a genetic variant p-value threshold below 5E-08 (n=32 studies) 25,31,32,35,37–40,43–49,51–61,64–70 , but an F-statistic ≥10 (n=27 studies) 25,32–36,38,44,47–49,51,53,55–60,62–65,67,68,70 , and had a high percentage (≥3%) of explained variance (n=11 studies) 32,35,38,51,55,58,60,62,64,66 , providing good evidence that the chosen instrument was robust.…”

“…A pre-specified subgroup analysis was performed to estimate the associations of genetically predicted adiposity measures with mental illnesses stratified by sex. In Appendix , seven studies with 76 estimates provided the associations of genetically predicted BMI with depression and anxiety by sex 25,43,57,59,70 . In Figure 4A , there is no evidence from a meta-analysis including 18 MR estimates that the causal relationship between BMI and depression differed by sex (P=0.313).…”

“…We repeated the main analyses estimating the association of genetically predicted adiposity with depression including only studies that reported results with binary outcomes. In Appendix , nine studies with 15 estimates provided results with binary outcomes (OR 1.06, 95% CI 1.00-1.13) 33,50,57,58,63,64,67,69,70 . The findings were similar to the main analysis which included binary and continuous outcomes ( Figure 5 ).…”

Weight stigma, welfare stigma, and political values: evidence from a representative British survey

“…A crucial question is whether these relationships are culturally specific to the UK. Cross-cultural work suggests that a high BMI raises risk of depression in some cultures but protects against depression in others, depending on its cultural significance (86). Similarly, attitudes around obesity may differ in contexts where thinness, rather than obesity, have been historically linked to socioeconomic disadvantage and ill-health.…”