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Genetic Studies ID Variants Behind Blood-Related Traits

NEW YORK (GenomeWeb News) – Four papers published in the advance, online issue of Nature Genetics yesterday are offering new insights into the genetics of blood-related traits as well as ties between these genetic variants and disease risk factors.

In the first of these papers, members of the HaemGen Consortium did a genome-wide association study for eight blood-related traits — including everything from hemoglobin concentration to red and white blood cell and platelet counts and volumes — in 13,943 individuals from six groups of Europeans.

"Until now, few genome-wide association studies have looked beyond single traits," co-senior author Christian Geiger, a genetic epidemiologist at the German Research Center for Environmental Health's Institute of Epidemiology, said in a statement. "But, through a systematic analysis of correlated traits we can begin to discover such shared genetic variants, forming the basis for understanding how these processes interact to influence health and disease."

In the first phase of the study, the team, led by researchers at the Wellcome Trust Sanger Institute and the Helmholtz Zentrum Munich, German Research Center for Environmental Health, genotyped 4,627 individuals at more than two million genotyped and imputed SNPs using three Affymetrix and Illumina platforms. They then honed in on the top 88 loci, which they tested in another 9,316 individuals.

Overall, the researchers identified 22 regions associated with blood traits, including 15 that hadn't been identified in previous studies. Six were linked to red blood cell traits and one was linked to white blood cell counts. The team also detected 15 regions associated with platelet volume and function.

In their subsequent experiments, the team also demonstrated that at least some of the blood-related variants they identified — including two on chromosome 12 — are part of a shared haplotype also linked to coronary artery disease, myocardial infarction, type 1 diabetes, hypertension, and celiac disease risk.

"We have uncovered a novel variant linking platelet counts with heart attacks," co-lead author Nicole Soranzo, a researcher affiliated with the Wellcome Trust Sanger Institute and King's College London, said in a statement. "Further characterization of the regions uncovered in this study has the potential to improve our understanding how blood cell development is linked with human diseases, including blood cell cancers."

Meanwhile, researchers from an international research collaboration called the CHARGE Consortium did a GWAS looking specifically for variants influencing six red blood traits.

The team's meta-analysis of 24,167 individuals of European ancestry from several American and European studies turned up 45 SNPs at 23 different loci that were associated with red blood cell traits such as corpuscular volume, hemoglobin concentration, and so on. Six of the loci had been previously implicated as quantitative trait loci while 17 were new.

They subsequently validated these findings in a meta-analysis involving 9,456 participants from the HaemGen Consortium and a combined analysis of CHARGE and HaemGen data.

Similar to the results reported by the HaemGen Consortium, the CHARGE researchers found overlap between blood-related variants on chromosome 12 and those influencing blood pressure and hypertension.

In another Nature Genetics paper, researchers from Australia, the US, and the Netherlands used Illumina Human610-Quadv1 and HumanCNV370-Quadv3 chips to genotype 2,516 adolescents and 2,302 adults from nearly 2,300 Australian families that contained at least one set of twins to look for variants association with blood iron levels and red blood cell volume.

In so doing, they identified associations between iron levels in blood serum and SNPs in a gene called TMPRSS6, also known to play a role in a blood condition called iron-refractory iron-deficiency anemia.

The researchers' additional experiments suggest variants in TMPRSS6 and other SNPs identified in the study contribute to blood iron levels as well as red blood cell production and volume.

For their part, another team of researchers from the US, UK, and Finland implicated seven TMPRSS6 variants in an additional iron-related function: maintaining blood hemoglobin levels.

In their GWAS involving 6,316 individuals of European ancestry and 9,685 individuals of Indian-Asian ancestry that team identified four TMPRSS6 variants that were significantly associated with hemoglobin levels in Europeans and three associated in Indian Asians. When the team did a combined analysis of data from the European and Indian Asian populations, they found ten SNPs in TMPRSS6 and six in a gene called HFE that were associated with hemoglobin levels.

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