The Enigma of Finnish and Sardinian Type 1 Diabetes Incidence: Where Population History Meets Genetics

Finland and Sardinia have very high incidences of autoimmune type 1 diabetes (T1D), particularly in children, far exceeding those of other European countries—an enigma that has persisted for some forty years. Genetics has so far had only the established T1D-predisposing variants to work with: HLA, INS, and the roughly 80 GWAS loci. But the allele frequencies of these variants, comparable to those of other European populations, could not credit genetics with any particular role in the super-incidence. Notably, on published haplotype frequencies, HLA class II would place Sardinian incidence below the Finnish, whereas it stands some forty per cent above it, and no published comparison of class II frequencies across European populations accounts for the incidence gradient either. This is deeply frustrating, since the two populations have a highly distinctive history, making them uniquely isolated genetic outliers at the margins of Europe. In 2017, a seminal paper changed the picture by establishing the omnigenic model of human quantitative traits, which we apply here to T1D endotypes. This model rests on thousands, even tens of thousands, of rare, mostly non-coding and regulatory variants in the nuclear genome, each with a vanishingly small predisposing effect, invisible to T1D GWAS. Recently, this thinking has been extended by the stratagenic model, in which numerous rare variants act across diverse biological pathways such as those that compose T1D pathophysiology. Imagining how the history of the two populations could have produced rare, pathway-stratified genomic variants offers a plausible explanation for the super-incidence. Because the founder event itself displaces allele frequencies without direction, what founder history alone predicts is not high incidence but wide dispersion of incidence—Sardinia and Finland above the continental populations, Iceland below. Where prolonged selection is superimposed upon the founding draw, as malaria was in Sardinia and perhaps the famine in Finland, a direction can be added to that dispersion. We present and attempt to justify this hypothesis, state the observations that would refute it, and discuss the causal role of environment, which is a subject that has driven much epidemiological research in both Finland and Sardinia.