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

The genetic basis, heritability, and genetic differences by patterns and titers of antinuclear antibodies (ANA) are still poorly understood.

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.

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.

HLA-DQB1:0201, HLA-DRB1:03, HLA-B, and HLA-C were strong genetic factors for ANA+ in these European ancestry individuals.