Large-Scale Multi-Ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure

As these GEITP pages have often emphasized –– complex diseases, quantitative phenotypes such as height or body mass index, drug efficacy or adverse effects, or toxicity caused by environmental agents –– are almost always examples of multifactorial traits. The phenotype of blood pressure is an excellent example of a multifactorial trait (i.e. contributions from hundreds if not thousands of genes, plus epigenetic effects, plus environmental factors such as lifestyle and diet). Blood pressure is known to be partially under genetic control (heritability index = 30% – 60%). However, only a very small fraction of the heritability has been explained by single-nucleotide variants (SNVs) identified through genome-wide association studies (GWAS): i.e. only between 0.5% and 3.5% in various GWAS of several different ethnic groups.

Incorporating interactions between genetic variants and environmental exposures (GxE) represents an additional approach to discovering genetic effects on multifactorial traits. Understanding these interactions may more generally extend our knowledge of the genetic architecture (the total underlying genetic basis of any trait including all variants pertaining to that trait) of complex traits. Many lifestyle factors (e.g. amount of physical activity, tobacco use, alcohol consumption, stress, dietary factors, and prescription drugs) influence blood pressure. The recently established Gene-Lifestyle Interactions Working Group within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium has designed a series of multi-ancestry genome-wide interaction projects focused on assessing the impact of interactions with multiple lifestyle factors on genetics of cardiovascular traits.

Authors [see attached report] performed a genome-wide association meta-analysis, incorporating gene-smoking interactions to identify systolic- and diastolic-associated loci and to understand the modulating role of cigarette smoking in the genetic architecture of blood pressure. Studying a total of 610,091 individuals from five ancestral groups is shown herein to provide adequate statistical power for discovery of new genes. “Stage 1” analysis examined ~18.8 million SNVs and small insertion/deletion (indel) variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) –– with follow-up “Stage 2” analysis of promising variants in 480,178 additional individuals from five ancestries. Authors identified 15 loci that showed genome-wide significance (P < 5 x 10–8) in Stage 1 and formally replicated in Stage 2. A combined Stages 1 and 2 meta-analysis identified 66 additional genes having genome-wide significance. This MASSIVE STUDY (notice the number of coauthors in the many hundreds; this is definitely not a 'hunter-gatherer', but rather an 'agricultural community' research project) underscores the likelihood that multifactorial traits involve a very large number of genes. Clearly, the larger the cohort, the more discovered genes will reach statistical significance..!! Am J Hum Genet Mar 2o18; 102: 375–400

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