Whole-exome sequencing (WES) — of Finnish isolated populations — enhances rare-variant association power

Most alleles (recall that each gene has two ‘alleles’, one from each parent, and one on each chromosome of the chromosomal pair) — having demonstrated deleterious effects on phenotypes (traits; e.g. height, body mass index, type-2 diabetes, schizophrenia) — directly alter the structure or function of a protein. Whole-exome sequencing [(WES); which will detect single-nucleotide variants (SNVs) that change the amino acid sequence of a protein, because exomes represent DNA that is transcribed into RNA and subsequently translated into protein] aims to discover such alleles and to demonstrate their association with disease-related quantitative traits and complex diseases. However, WES to date generally have identified few newly associated rare variants or genes; this is likely because the sample size required for such discoveries must be very large.

Theoretical analyses indicate that WES studies to date have been statistically underpowered, because most harmful SNVs are expected to be rare — owing to purifying selection [during evolution of a species, ‘positive selection’ means accepting SNVs that benefit survival (ability to find food, reproduce, and avoid predators), whereas ‘purifying (or negative) selection’ is the default process of ‘elimination of the unfit’, i.e. SNVs are ‘tolerated’ only if they do not confer a significant disadvantage to survival of the species]. These previous analyses also suggest that the statistical power to detect an association with a deleterious allele — is highest in populations that have expanded in isolation, after recent “bottlenecks” — for the reason that alleles surviving a population bottleneck may increase to much higher frequencies, compared with other populations not experiencing any bottleneck.

Finland exemplifies such a history: bottlenecks occurred at the founding of early-settlement regions (south, and west, portions of the country) 2,000 to 4,000 years ago, and again with internal migration to late-settlement regions (north, and east, portions) in the 15th and 16th centuries. Finland’s subsequent population growth (to about 5.5 million) generated sizable geographical sub-isolates in late-settlement regions. This unique population history has resulted in ‘the Finnish Disease Heritage’, which found that 36 Mendelian diseases are much more common in Finnish individuals than in other Europeans. These disorders are located mostly in late-settlement regions of Finland, and the genes responsible for them exhibit extreme enrichment of undesirable SNVs.

Authors [see attached article] created the Finnish Metabolic Sequencing (FinMetSeq) study — to capitalize on the population history of late-settlement Finland; authors were thus able to discover rare-variant associations with cardiovascular and metabolic disease-relevant quantitative traits via WES of two extensively phenotyped population cohorts, FINRISK and METSIM. Carrying out WES in almost 20,000 individuals from the northern and eastern regions, authors found rare coding SNVs in 26 newly associated deleterious alleles that are clinically relevant to 64 quantitative cardiometabolic traits [see Figure 1 of attached article]. Of these 26 alleles, 19 are either unique to, or more than 20 times more frequent in, Finnish individuals than in other Europeans. Geographical clustering — comparable to that seen with Mendelian disease mutations — were demonstrated to be characteristic of the Finnish population. Authors estimated that sequencing studies of populations without this unique history would require hundreds of thousands, to millions, of participants to achieve comparable statistical association power..!! 😊

Nature 15 Aug 2019; 572: 323-328

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