Multi-ancestry GWAS of Long COVID identifies immune-related loci and etiological links to chronic fatigue syndrome, fibromyalgia and depression

The etiology of Long COVID is poorly understood despite its estimated global burden of 65 million cases. There exists a paucity of genetic studies that can shed light on potential mechanisms leading to Long COVID. Using consented and genotyped data from 23andMe adult research participants, we conducted the largest multi-ancestry meta-analysis of genome-wide association studies of Long COVID across European (42,899 cases, 94,721 controls), Latinx (8,631 cases, 20,351 controls), and African-American (2,234 cases, 5,596 controls) genetic ancestry groups. GWAS of Long COVID identified three genome-wide significant loci ( HLA-DQA1–HLA-DQB, ABO, BPTF–KPAN2 – C17orf58 ). Functional analysis of these genes points to underlying immune and thrombo-inflammatory mechanisms. We present evidence of shared genetic architecture (genetic correlation p-value < 0.001) of Long COVID with thirteen phenotypes of similar symptomatology or pathophysiology. We identified potential causal roles from liability to chronic fatigue (Mendelian randomization OR=1.59, 95% CI[1.51,1.66]), fibromyalgia (OR=1.54, 95% CI[1.49,1.60]), and depression (OR=1.53, 95% CI[1.46,1.61]) with Long COVID, which replicated in the COVID-19 Host Genetics Initiative data, and which are unlikely to originate from collider bias. These findings can help identify populations vulnerable to Long COVID and inform future therapeutic approaches.