Comprehensive X-chromosome association analysis identifies novel genetic associations with dietary intake

Despite the importance of healthy diet, adherence to dietary recommendations remains low. This may reflect individual differences in dietary intake that arise from environmental and genetic factors, including hormonal regulation, sex differences, and biological drivers of food preference. Genome-wide association studies (GWAS) have identified hundreds of loci associated with dietary intake, but the X-chromosome, a major source of sex-linked genetic variation, has largely been excluded. We applied multiple X-chromosome-wide association study (X-WAS) models to dietary intake phenotypes to identify novel loci and sex-specific effects. We performed X-WAS of 46 dietary intake traits from food frequency questionnaires in European-ancestry UK Biobank (UKB) participants ( N = 424,758). Phenotypes included quantitative measures (e.g., fruit intake), binary traits (e.g., decaffeinated vs. caffeinated coffee), and principal component-derived food groups. We tested five X-WAS models: a traditional sex-combined additive model, sex-stratified additive models, a joint model that accounts for sex-interactions, and a model for non-additive genetic effects. We assessed generalizability across six ancestry groups, conducted a multi-ancestry meta-analysis ( N = 445,773), and sought replication of female-specific findings in Women’s Genome Health Study (WGHS; N = 23,129). To characterize the biological context of associated loci, we performed phenome-wide association studies and covariate sensitivity analysis of known confounders of diet. We identified 18 loci associated with 20 dietary traits ( P <5 × 10 − 8 ), including two with prior evidence of biological mechanisms related to dietary behavior ( GPR173 and HTR2C ). Five loci had stronger associations in models accounting for sex-specific effects, including one locus with a significant SNP-by-sex interaction (rs191475305 associated with meat intake), highlighting the importance of considering unique X-chromosome biology. Eight of nine tested loci demonstrated consistent effects across ancestry groups in UKB (heterogeneity P > 0.05), and two of six loci replicated in WGHS ( P < 0.05). Our study uncovers novel loci associated with dietary intake and provides evidence that sex-linked genetic variation contributes to individual differences in dietary intake. While most associations were detectable using conventional sex-combined analyses, models accounting for sex-specific and non-additive effects produced the strongest associations on several occasions. These findings establish the X-chromosome as an important component of dietary intake genetic architecture and demonstrate the value of robust X-chromosome models for genetic discovery.