Effect of parental autoimmune diseases on type 1 diabetes in offspring can be partially explained by HLA and non-HLA polymorphisms: a nationwide registry and biobank-based study in 7.2M Finns

Type 1 diabetes (T1D) and other autoimmune diseases (AIDs) co-occur in families. We studied the aggregation of 50 parental AIDs with T1D in offspring and the contribution of a shared genetic background, which was partitioned into HLA and non-HLA variation. Leveraging nationwide registers of 7.2M Finns, including 58,284 family trios, we observed that 15 parental AIDs, such as coeliac disease and rheumatoid arthritis, were associated with an increased risk of T1D in offspring. The identified epidemiological associations were then tested by comprehensive genetic analyses performed on 470K Finns genotyped in the FinnGen study (12,563 trios). The within-family genetic transmission analysis further demonstrated that the aggregation of parental AIDs with offspring T1D could be partially explained by HLA and non-HLA polymorphisms in a disease-dependent manner. For example, the associations with offspring T1D for coeliac disease and psoriasis were mainly driven by HLA while autoimmune hypothyroidism and rheumatoid arthritis also had non-HLA contributors. We, therefore, proposed a novel parental polygenic score (PGS), integrating variations in both HLA and non-HLA genes, to understand the cumulative risk pattern of T1D in offspring. This raises an intriguing possibility of considering parental PGS, in conjunction with clinical diagnoses, to inform individuals about T1D risk in their offspring.