Seven replicated genomic associations of myalgic encephalomyelitis/chronic fatigue syndrome: a biobank study

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating female-biased disease with neither diagnostic biomarker nor effective treatment nor well-understood aetiology. To investigate its biological basis, we used TarGene to perform a genome-wide association study in the UK Biobank with 1,268 ME/CFS cases, using electronic health records and survey responses to affirm ME/CFS status in cases, and non-ME/CFS status in controls. This analysis identified 176 variants as significantly associated with ME/CFS (false discovery rate < 5%). We then performed two replication studies, with similar phenotyping, in two disjoint, smaller cohorts in the UK Biobank and in the All of Us Research Program with 319 and 371 cases, respectively. Seven genomic ME/CFS risk loci replicated, although none were significant across all three cohorts. Fine-mapping at one replicated locus resolved a credible set colocalising with reduced CLYBL expression in putamen, in linkage disequilibrium with the replicated variant. However, the CLYBL Arg259 stop-gain variant was not associated with ME/CFS risk. Other replicated loci contained BICD1, GRIN2A, CSMD1 and RORA genes. No gene-by-sex or gene-by-deprivation interactions survived multiple-testing correction.