Genetic characterization of Greek population isolates reveals strong genetic drift at missense and trait-associated variants

Citations Over TimeTop 10% of 2014 papers

Abstract

Isolated populations are emerging as a powerful study design in the search for low-frequency and rare variant associations with complex phenotypes. Here we genotype 2,296 samples from two isolated Greek populations, the Pomak villages (HELIC-Pomak) in the North of Greece and the Mylopotamos villages (HELIC-MANOLIS) in Crete. We compare their genomic characteristics to the general Greek population and establish them as genetic isolates. In the MANOLIS cohort, we observe an enrichment of missense variants among the variants that have drifted up in frequency by more than fivefold. In the Pomak cohort, we find novel associations at variants on chr11p15.4 showing large allele frequency increases (from 0.2% in the general Greek population to 4.6% in the isolate) with haematological traits, for example, with mean corpuscular volume (rs7116019, P=2.3 × 10(-26)). We replicate this association in a second set of Pomak samples (combined P=2.0 × 10(-36)). We demonstrate significant power gains in detecting medical trait associations.

Related Papers

• → Molecular Mechanisms and Clinical Phenotypes of GJB2 Missense Variants(2023)15 cited
• → Missense mutations and the magnitude of functional deficit: the example of factor IX(1992)19 cited
• → Regional missense constraint improves variant deleteriousness prediction(2017)391 cited
• → Abstract P2-02-03: Optimized prediction of deleterious missense mutations in BRCA1 and BRCA2 genes(2017)
• → Evaluation of cancer related missense mutations in CENPH(2019)