Body mass index and psychiatric disorders: a Mendelian randomization study

Abstract

Obesity is a highly prevalent risk factor for cardiometabolic diseases. Observational studies suggest that obesity is associated with psychiatric traits, but causal inference from such studies has several limitations. We used two-sample Mendelian randomization methods (inverse variance weighting, weighted median and MR-Egger regression) to evaluate the association of body mass index (BMI) with three psychiatric traits using data from the Genetic Investigation of Anthropometric Traits and Psychiatric Genomics consortia. Causal odds ratio estimates per 1-standard deviation increment in BMI ranged from 0.88 (95% CI: 0.62; 1.25) to 1.23 (95% CI: 0.65; 2.31) for bipolar disorder; 0.93 (0.78; 1.11) to 1.41 (0.87; 2.27) for schizophrenia; and 1.15 (95% CI: 0.92; 1.44) to 1.40 (95% CI: 1.03; 1.90) for major depressive disorder. Analyses removing potentially influential SNPs suggested that the effect estimates for depression might be underestimated. Our findings do not support the notion that higher BMI increases risk of bipolar disorder and schizophrenia. Although the point estimates for depression were consistent in all sensitivity analyses, the overall statistical evidence was weak. However, the fact that SNP-depression associations were estimated in relatively small samples reduced power to detect causal effects. This should be re-addressed when SNP-depression associations from larger studies become available.

Genome wide meta-analysis identifies genomic relationships, novel loci, and pleiotropic mechanisms across eight psychiatric disorders

“…In addition, the pleiotropic risk loci were enriched among genes previously associated with neuroticism (corrected enrichment p= 5.28x10 -6 ; GRIK3, CTNND1,DRD2,RGS6,RBFOX1,ZNF804A,L3MBTL2,CHADL,RANGAP1,RSRC1,GRM3), cognitive ability (corrected p= 7.15x10 -5 ; PTPRF, NEGR1, ELOVL3, SORCS3, DCC, CACNA1I), and night sleep phenotypes (corrected p= 1.86x10 -2 ; PBX1, NPAS3, RGS6,GRIN2A,MYO18A,TIAF1,CNTN4,PPP2R2B,TENM2,CSMD1). We also found significant enrichment of pleiotropic risk genes in multiple measures of body mass index (BMI), supporting previous studies suggesting a shared etiologic basis between a range of neuropsychiatric disorders and obesity (Hartwig et al, 2016;Lopresti and Drummond, 2013;Milaneschi et al, 2018)…”

Using Mendelian randomisation to assess causality in observational studies

“…All estimates are reported per 1 SD increase of BMI. The data used in this example are obtained from a published study of Hartwig and coworkers 17. BMI, body mass index; IVW, inverse-variance weighted; ML, maximum likelihood; P-het, Cohrans’s Q p value; SNPs, single-nucleotide polymorphisms.…”

“…The data used in this example are obtained from a published study of Hartwig and coworkers 17. BMI, body mass index; logOR, natural logarithm of OR.…”

Environmental risk factors and nonpharmacological and nonsurgical interventions for obesity: An umbrella review of meta‐analyses of cohort studies and randomized controlled trials

“…50 Initial Mendelian randomization (MR) studies using weak genetic instruments did not appear to support a causal association between higher BMI and incident depression, 109,110 but one more recent study has suggested a 1.15-fold to 1.40-fold higher risk of depression for each standard deviation increase in BMI. 111 To our knowledge, the inverse association (whether depression causes obesity) has not been assessed in published MR studies to date.…”