Genome-wide association study for loci associated with positive antinuclear antibodies

Background: The genetic basis, heritability, and genetic differences by patterns and titers of antinuclear antibodies (ANA) are still poorly understood. Methods: Within the Mass General Brigham Biobank, containing electronic health records (EHR) and genotyping for >65,000 consented patients, we identified individuals with HEp-2 immunofluorescence ANA results (1989–2022) and genetically predicted European ancestry. We performed genome-wide associated studies for ANA+ ≥ 1:40, ≥ 1:80, all and in speckled and homogeneous ANA patterns, for those only +1:40, and then excluding those with ≥1 of 9 ANA-associated autoimmune diagnoses, each compared to those ANA- and adjusted for age, sex, and 4 genetic principal components. The lability method estimated ANA+ heritability. We investigated HLA alleles using SNP2HLA imputation. Results: 7035 subjects were ANA+ at ≥1:40, 4279 at ≥1:80 and 5840 were ANA -. Associations were similar but stronger for ANA ≥1:80 than ≥1:40. Associations were stronger for speckled and homogeneous ANA patterns separately (each vs. all ANA-) and attenuated after excluding those with ≥1 autoimmune disease diagnosis. At both titers, HLA-DQB1:0201 had the strongest association, OR 1.3 (95 % CI 1.2–1.5, p 9.1 × 10^–14 for ANA ≥1:80); HLA-B:08, HLA-DRB1:03, and HLA:C:0701 alleles also showed significant associations. The strongest non-HLA association was rs34748780 (chromosome 7) near IRF5/TNPO3, OR 1.2 (95 % CI 1.1–1.4, p 1.6 × 10^–8 for ANA ≥1:80). ANA+ ≥1:40 heritability was 12 % (SE 0.03), p 1.0 × 10^–8 and ≥1:80 was 19 % (SE 0.03), p 1.9 × 10^–12. Conclusion: HLA-DQB1:0201, HLA-DRB1:03, HLA-B, and HLA-C were strong genetic factors for ANA+ in these European ancestry individuals.