Exome sequencing of Finnish isolates enhances rare-variant association power.

Abstract

Exome sequencing studies have generally been underpowered to identify deleterious alleles with a large effect on complex traits, as such alleles are mostly rare. Because the population of northern and eastern Finland has expanded dramatically and in isolation following a series of bottlenecks, it harbors numerous deleterious alleles at relatively high frequency. Capitalizing on this circumstance, we exome sequenced nearly 20,000 individuals from these regions. Exome-wide association studies for 64 quantitative traits clinically relevant to cardiovascular and metabolic disease identified 26 newly associated deleterious alleles. Nineteen of these alleles are either unique to or >20 times more frequent in Finns than in other Europeans and show geographical clustering comparable to Mendelian disease mutations characteristic of the Finnish population. We estimate that sequencing studies in populations without this unique history would require hundreds of thousands to millions of participants to achieve comparable association power.