Title | Practical Approaches for Whole-Genome Sequence Analysis of Heart- and Blood-Related Traits. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Morrison, AC, Huang, Z, Yu, B, Metcalf, GA, Liu, X, Ballantyne, C, Coresh, J, Yu, F, Muzny, DM, Feofanova, E, Rustagi, N, Gibbs, RA, Boerwinkle, E |
Journal | Am J Hum Genet |
Volume | 100 |
Issue | 2 |
Pagination | 205-215 |
Date Published | 2017 Feb 02 |
ISSN | 1537-6605 |
Keywords | Black or African American, C-Reactive Protein, Cholesterol, HDL, Cholesterol, LDL, Chromosomes, Human, Pair 9, Gene Frequency, Genome, Human, Genome-Wide Association Study, Genomics, Hemoglobins, Humans, Introns, Leukocyte Count, Lipoprotein(a), Magnesium, Natriuretic Peptide, Brain, Neutrophils, Peptide Fragments, Phosphorus, Platelet Count, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Troponin T, White People |
Abstract | Whole-genome sequencing (WGS) allows for a comprehensive view of the sequence of the human genome. We present and apply integrated methodologic steps for interrogating WGS data to characterize the genetic architecture of 10 heart- and blood-related traits in a sample of 1,860 African Americans. In order to evaluate the contribution of regulatory and non-protein coding regions of the genome, we conducted aggregate tests of rare variation across the entire genomic landscape using a sliding window, complemented by an annotation-based assessment of the genome using predefined regulatory elements and within the first intron of all genes. These tests were performed treating all variants equally as well as with individual variants weighted by a measure of predicted functional consequence. Significant findings were assessed in 1,705 individuals of European ancestry. After these steps, we identified and replicated components of the genomic landscape significantly associated with heart- and blood-related traits. For two traits, lipoprotein(a) levels and neutrophil count, aggregate tests of low-frequency and rare variation were significantly associated across multiple motifs. For a third trait, cardiac troponin T, investigation of regulatory domains identified a locus on chromosome 9. These practical approaches for WGS analysis led to the identification of informative genomic regions and also showed that defined non-coding regions, such as first introns of genes and regulatory domains, are associated with important risk factor phenotypes. This study illustrates the tractable nature of WGS data and outlines an approach for characterizing the genetic architecture of complex traits. |
DOI | 10.1016/j.ajhg.2016.12.009 |
Alternate Journal | Am J Hum Genet |
PubMed ID | 28089252 |
PubMed Central ID | PMC5294677 |
Grant List | HHSN268201100012C / HL / NHLBI NIH HHS / United States RC2 HL102419 / HL / NHLBI NIH HHS / United States HHSN268201100009I / HL / NHLBI NIH HHS / United States HHSN268201100010C / HL / NHLBI NIH HHS / United States HHSN268201100008C / HL / NHLBI NIH HHS / United States HHSN268201100005G / HL / NHLBI NIH HHS / United States HHSN268201100008I / HL / NHLBI NIH HHS / United States HHSN268201100007C / HL / NHLBI NIH HHS / United States HHSN268201100011I / HL / NHLBI NIH HHS / United States HHSN268201100011C / HL / NHLBI NIH HHS / United States U54 HG003273 / HG / NHGRI NIH HHS / United States HHSN268201100006C / HL / NHLBI NIH HHS / United States HHSN268201100005I / HL / NHLBI NIH HHS / United States HHSN268201100009C / HL / NHLBI NIH HHS / United States HHSN268201100005C / HL / NHLBI NIH HHS / United States HHSN268201100007I / HL / NHLBI NIH HHS / United States UM1 HG008898 / HG / NHGRI NIH HHS / United States / RA / ARRA NIH HHS / United States |
Practical Approaches for Whole-Genome Sequence Analysis of Heart- and Blood-Related Traits.
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