Leveraging nationwide health care records in Estonia to identify the genetic background of understudied disease phenotypes
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Nationwide health records linked to population biobanks can expand genetic discovery into clinical phenotypes that are poorly captured in hospital-centred datasets. We performed genome-wide association analyses of 5,491 ICD-10-based disease phenotypes in 206,159 Estonian Biobank participants using imputed genotype data across 18.8 million single-nucleotide and insertion-deletion variants.
Across the disease phenome, we identified 3,222 genome-wide significant loci, with strongest added value for outpatient-enriched, recurrent, and earlier-onset conditions. Fine-mapping prioritised candidate causal variants across study-wide significant loci, while coding variant analyses identified 754 protein-altering variant-trait associations outside the HLA region, including high-confidence signals in various dermatological, anaemia, congenital, and metabolic traits. A separate HLA analysis identified 744 HLA-trait associations across infectious, autoimmune, and skin-related phenotypes.
As an example of discovery in an understudied phenotype, we highlight pityriasis versicolor, a superficial fungal infection with 34 loci in EstBB-FinnGen meta-analysis, including a rare Estonian-enriched splice-disrupting TNFSF15 variant. These results establish EstBB as a resource for mapping genetic architecture across clinically diverse and underrepresented disease phenotypes.
