|Title||Assessing the contribution of rare genetic variants to phenotypes of chronic obstructive pulmonary disease using whole-genome sequence data.|
|Publication Type||Journal Article|
|Year of Publication||2022|
|Authors||Kim, W, Hecker, J, R Barr, G, Boerwinkle, E, Cade, B, Correa, A, Dupuis, J, Gharib, SA, Lange, L, London, SJ, Morrison, AC, O'Connor, GT, Oelsner, EC, Psaty, BM, Vasan, RS, Redline, S, Rich, SS, Rotter, JI, Yu, B, Lange, C, Manichaikul, A, Zhou, JJ, Sofer, T, Silverman, EK, Qiao, D, Cho, MH|
|Corporate Authors||NHLBI Trans-Omics in Precision Medicine (TOPMed) Consortium and TOPMed Lung Working Group|
|Journal||Hum Mol Genet|
|Date Published||2022 Nov 10|
|Keywords||Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Phenotype, Polymorphism, Single Nucleotide, Pulmonary Disease, Chronic Obstructive|
RATIONALE: Genetic variation has a substantial contribution to chronic obstructive pulmonary disease (COPD) and lung function measurements. Heritability estimates using genome-wide genotyping data can be biased if analyses do not appropriately account for the nonuniform distribution of genetic effects across the allele frequency and linkage disequilibrium (LD) spectrum. In addition, the contribution of rare variants has been unclear.
OBJECTIVES: We sought to assess the heritability of COPD and lung function using whole-genome sequence data from the Trans-Omics for Precision Medicine program.
METHODS: Using the genome-based restricted maximum likelihood method, we partitioned the genome into bins based on minor allele frequency and LD scores and estimated heritability of COPD, FEV1% predicted and FEV1/FVC ratio in 11 051 European ancestry and 5853 African-American participants.
MEASUREMENTS AND MAIN RESULTS: In European ancestry participants, the estimated heritability of COPD, FEV1% predicted and FEV1/FVC ratio were 35.5%, 55.6% and 32.5%, of which 18.8%, 19.7%, 17.8% were from common variants, and 16.6%, 35.8%, and 14.6% were from rare variants. These estimates had wide confidence intervals, with common variants and some sets of rare variants showing a statistically significant contribution (P-value
CONCLUSIONS: Our study provides updated and unbiased estimates of heritability for COPD and lung function, and suggests an important contribution of rare variants. Larger studies of more diverse ancestry will improve accuracy of these estimates.
|Alternate Journal||Hum Mol Genet|
|PubMed Central ID||PMC9652112|
|Grant List||HHSN268201100037C / HL / NHLBI NIH HHS / United States |
R21 HL153700 / HL / NHLBI NIH HHS / United States
R01 HG006139 / HG / NHGRI NIH HHS / United States
R01 HL153805 / HL / NHLBI NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
U01 HL089856 / HL / NHLBI NIH HHS / United States
R21 HL129924 / HL / NHLBI NIH HHS / United States
HHSN268201500014C / HL / NHLBI NIH HHS / United States
R03 HL154284 / HL / NHLBI NIH HHS / United States
K23 HL130627 / HL / NHLBI NIH HHS / United States