Combined Genome Scans for Body Stature in 6,602 European Twins: Evidence for Common Caucasian Loci

Abstract

Twin cohorts provide a unique advantage for investigations of the role of genetics and environment in the etiology of variation in common complex traits by reducing the variance due to environment, age, and cohort differences. The GenomEUtwin ( http://www.genomeutwin.org) consortium consists of eight twin cohorts (Australian, Danish, Dutch, Finnish, Italian, Norwegian, Swedish, and United Kingdom) with the total resource of hundreds of thousands of twin pairs. We performed quantitative trait locus (QTL) analysis of one of the most heritable human complex traits, adult stature (body height) using genome-wide scans performed for 3,817 families (8,450 individuals) derived from twin cohorts from Australia, Denmark, Finland, Netherlands, Sweden, and United Kingdom with an approximate ten-centimorgan microsatellite marker map. The marker maps for different studies differed and they were combined and related to the sequence positions using software developed by us, which is publicly available ( https://apps.bioinfo.helsinki.fi/software/cartographer.aspx). Variance component linkage analysis was performed with age, sex, and country of origin as covariates. The covariate adjusted heritability was 81% for stature in the pooled dataset. We found evidence for a major QTL for human stature on 8q21.3 (multipoint logarithm of the odds 3.28), and suggestive evidence for loci on Chromosomes X, 7, and 20. Some evidence of sex heterogeneity was found, however, no obvious female-specific QTLs emerged. Several cohorts contributed to the identified loci, suggesting an evolutionarily old genetic variant having effects on stature in European-based populations. To facilitate the genetic studies of stature we have also set up a website that lists all stature genome scans published and their most significant loci ( http://www.genomeutwin.org/stature_gene_map.htm).

Author Summary

Twin cohorts provide a unique advantage for research of the role of genetics and environment behind common complex traits by reducing the variance due to environment, age, and cohort differences. The GenomEUtwin consortium consists of eight twin cohorts with the total resource of hundreds of thousands of twin pairs ( http://www.genomeutwin.org). We performed quantitative family-based genetic linkage analysis for one of the most heritable human complex traits, adult stature (body height), using genome-wide scans derived from twin cohorts from Australia, Denmark, Finland, Netherlands, Sweden, and United Kingdom. Age, sex, and country were adjusted for in the data analyses. Human stature was found to be very heritable across all the cohorts and in the combined dataset. We found evidence for a shared genetic locus accounting for human stature on Chromosome 8, and suggestive evidence for loci on Chromosomes X, 7, and 20. Since twins from several countries contributed to the identified loci, an evolutionarily old genetic variant must influence stature in European-based populations. To facilitate the research in the field we have also set up a website that lists all stature genome scans published and their most significant loci ( http://www.genomeutwin.org/stature_gene_map.htm).