Mark Daly, Aarno Palotie and colleagues examined how genomic architecture in the Finnish founder population differs from that of other European populations (PLoS Genet. 10, e1004494, 2014). They analyzed the exome sequences of 3,000 Finnish individuals and 3,000 non-Finnish Europeans as part of the Sequencing Initiative Suomi (SISu) project. A higher proportion of low-frequency loss-of-function variants was identified in the exomes of the Finnish individuals. They selected 83 loss-of-function variants showing at least 2-fold enrichment in Finns and genotyped these variants in an additional 36,262 Finnish individuals from 3 population-based cohorts. They tested for association to 60 quantitative traits as well as 13 disease outcomes, making use of access to data form the National Health Registers. Variants were identified in the LPA gene (encoding lipoprotein(a)) that were associated with lower plasma lipoprotein(a) levels. Using a mendelian randomization approach, they found that the LPA variants were protective against coronary heart disease. These analyses suggest that a reduction in lipoprotein(a) levels provides a protective effect against cardiovascular diseases and highlight a possible drug target.