(P21-002-25) X-Chromosome-Wide Association Study of Dietary Intake in the UK Biobank Identifies 25 Genetic Loci That Influence Eating Behavior

Objectives: Though unhealthy dietary intake is a leading risk factor for many common diseases, adherence to common dietary recommendations is low because they do not incorporate the individual environmental or genetic drivers of food choice. Although genome-wide association studies (GWAS) have identified hundreds of genetic variants associated with diet, the X-chromosome has been ignored due to analytical challenges, even though it harbors genes that impact health. Here our objective is to apply multiple X-chromosome association study (X-WAS) models to tackle these analytical challenges and uncover novel associations on the X-chromosome.

Methods: We performed X-WAS and X-wide interaction studies by sex of 46 diet traits from Food Frequency Questionnaires in 425k European UK Biobank participants. Dietary traits included quantitative measures (e.g., fruit intake), binary traits (e.g., decaf vs caffeinated coffee), and principal component-derived dietary patterns. We tested for significant genetic effects in 3 strata (females, males, and all individuals), 2 additional joint models that account for sex differences or deviation from additivity, and sex-interaction effects.

Results: We identified 25 loci associated with 19 dietary traits (P  < 5x10^-8), including 22 variants which have no known associations with any trait. SNP rs11539157, a missense variant in the PJA1 gene is associated with beer and cider intake, alcohol intake frequency, alcohol consumption with meals, and cereal intake (all P  < 4x10^-10), and has previously been shown to be associated with carbohydrate intake, BMI, and smoking. SNP rs191475305 had a significant sex-interaction effect on meat consumption (P = 4x10^-9) and is in the WWC3 gene. Furthermore, 8 of our top loci were strongest when we employed more sophisticated models (i.e. sex-stratified, joint tests, or interaction tests) highlighting the importance of optimizing model performance for genomic discovery.

Conclusions: The X-chromosome harbors genetic variants with significant effects on dietary intake that have been missed in previous GWAS. Understanding the complete spectrum of genomic variation (including the X-chromosome) that impacts an individual’s food choice is critical to elucidating the biological mechanisms which drive eating behavior.

Funding Sources: This work was funded by the NIDDK of the National Institutes of Health.