Exploration of Shared Genetic Architecture Between Subcortical Brain Volumes and Anorexia Nervosa

E Walton,Stefan Ehrlich,Z Yilmaz,D Hibar,N Jahanshad,P M Thompson,J Cheung,V.-L Batury,J Seitz,C M Bulik

doi:10.1007/s12035-018-1439-4

Abstract

In MRI scans of patients with anorexia nervosa (AN), reductions in brain volume are often apparent. However, it is unknown whether such brain abnormalities are influenced by genetic determinants that partially overlap with those underlying AN. Here, we used a battery of methods (LD score regression, genetic risk scores, sign test, SNP effect concordance analysis, and Mendelian randomization) to investigate the genetic covariation between subcortical brain volumes and risk for AN based on summary measures retrieved from genome-wide association studies of regional brain volumes (ENIGMA consortium, n = 13,170) and genetic risk for AN (PGC-ED consortium, n = 14,477). Genetic correlations ranged from − 0.10 to 0.23 (all p > 0.05). There were some signs of an inverse concordance between greater thalamus volume and risk for AN (permuted p = 0.009, 95% CI: [0.005, 0.017]). A genetic variant in the vicinity of ZW10, a gene involved in cell division, and neurotransmitter and immune system relevant genes, in particular DRD2, was significantly associated with AN only after conditioning on its association with caudate volume (pFDR = 0.025). Another genetic variant linked to LRRC4C, important in axonal and synaptic development, reached significance after conditioning on hippocampal volume (pFDR = 0.021). In this comprehensive set of analyses and based on the largest available sample sizes to date, there was weak evidence for associations between risk for AN and risk for abnormal subcortical brain volumes at a global level (that is, common variant genetic architecture), but suggestive evidence for effects of single genetic markers. Highly powered multimodal brain- and disorder-related genome-wide studies are needed to further dissect the shared genetic influences on brain structure and risk for AN.

Highlights

Anorexia nervosa (AN) is an often life-threatening, adolescent-onset eating disorder characterized by severe emaciation, and typically by severe food restriction
The following analyses were based on summary statistics for (a) eight brain volume measures of 13,170 participants from the Enhancing NeuroImaging Genetics Through Meta-Analysis Consortium (ENIGMA) consortium and (b) AN case-control data from 3495 AN patients and 10,982 healthy individuals
Linkage disequilibrium score (LDSC) regression examines the relationship between two sets of genome-wide association studies (GWAS) test statistics using linkage disequilibrium

Summary

Introduction

Anorexia nervosa (AN) is an often life-threatening, adolescent-onset eating disorder characterized by severe emaciation, and typically by severe food restriction. Mol Neurobiol (2019) 56:5146–5156 pathophysiology of the disorder. A number of structural MRI studies (albeit with small sample sizes) have documented decreases in both gray and white matter volumes Larger studies and a meta-analysis have confirmed widespread gray matter volume reductions in AN, with regional effects especially in rewardrelated and somatosensory areas [9,10,11]. In weight-recovered patients, subcortical and cortical gray matter deficits seemed to normalize, but several studies have reported small group differences even after recovery [9, 12,13,14]

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Conclusion