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1.  Genome-wide Linkage Screen for Stature and Body-mass Index in 3.032 Families - Evidence for Sex- and Population-specific Genetic Effects 
Stature (adult body height), and body mass index (BMI) have a strong genetic component explaining observed variation in human populations, however, identifying those genetic components has been extremely challenging. It seems obvious that sample size is a critical determinant for successful identification of quantitative trait loci (QTL) that underlie the genetic architecture of these polygenic traits. The inherent shared environment and known genetic relationships in family studies provide clear advantages for gene mapping over studies utilizing unrelated individuals. To these ends, we combined the genotype and phenotype data from four previously performed family-based genome-wide screens resulting in a sample of 9.371 individuals from 3.032 African-American and European-American families and performed variance-components linkage analyses for stature and BMI. To our knowledge, this study represents the single largest family-based genome-wide linkage scan published for stature and BMI to date. This large study sample allowed us to pursue population-and sex-specific analyses as well. For stature we found evidence for linkage in previously reported loci on 11q23, 12q12, 15q25 and 18q23 as well as 15q26 and 19q13 which have not been linked to stature previously. For BMI we found evidence for two loci: one on 7q35 and another on 11q22 both of which have been previously linked to BMI in multiple populations. Our results show both the benefit of 1) combining data to maximize the sample size and 2) minimizing heterogeneity by analyzing subgroups where within-group variation can be reduced and suggest that the latter may be a more successful approach in genetic mapping.
doi:10.1038/ejhg.2008.152
PMCID: PMC2628452  PMID: 18781184
Body Height; Body Mass Index; Linkage mapping; Quantitative Trait Loci
2.  Genome-wide linkage screen for stature and body mass index in 3.032 families: evidence for sex- and population-specific genetic effects 
Stature (adult body height) and body mass index (BMI) have a strong genetic component explaining observed variation in human populations; however, identifying those genetic components has been extremely challenging. It seems obvious that sample size is a critical determinant for successful identification of quantitative trait loci (QTL) that underlie the genetic architecture of these polygenic traits. The inherent shared environment and known genetic relationships in family studies provide clear advantages for gene mapping over studies utilizing unrelated individuals. To these ends, we combined the genotype and phenotype data from four previously performed family-based genome-wide screens resulting in a sample of 9.371 individuals from 3.032 African-American and European-American families and performed variance-components linkage analyses for stature and BMI. To our knowledge, this study represents the single largest family-based genome-wide linkage scan published for stature and BMI to date. This large study sample allowed us to pursue population- and sex-specific analyses as well. For stature, we found evidence for linkage in previously reported loci on 11q23, 12q12, 15q25 and 18q23, as well as 15q26 and 19q13, which have not been linked to stature previously. For BMI, we found evidence for two loci: one on 7q35 and another on 11q22, both of which have been previously linked to BMI in multiple populations. Our results show both the benefit of (1) combining data to maximize the sample size and (2) minimizing heterogeneity by analyzing subgroups where within-group variation can be reduced and suggest that the latter may be a more successful approach in genetic mapping.
doi:10.1038/ejhg.2008.152
PMCID: PMC2628452  PMID: 18781184
body height; body mass index; linkage mapping; quantitative trait loci
3.  Combined Genome Scans for Body Stature in 6,602 European Twins: Evidence for Common Caucasian Loci 
PLoS Genetics  2007;3(6):e97.
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).
doi:10.1371/journal.pgen.0030097
PMCID: PMC1892350  PMID: 17559308

Results 1-3 (3)