Abstract
Homozygosity for the SERPINA1 Z allele causes α1-antitrypsin deficiency, a rare condition that can cause lung and liver disease. However, the effects of Z allele heterozygosity on nonrespiratory phenotypes, and on lung function in the general population, remain unclear.We conducted a large, population-based study to determine Z allele effects on >2400 phenotypes in the UK Biobank (N=303 353).Z allele heterozygosity was strongly associated with increased height (β=1.02 cm, p=3.91×10−68), and with other nonrespiratory phenotypes including increased risk of gall bladder disease, reduced risk of heart disease and lower blood pressure, reduced risk of osteoarthritis and reduced bone mineral density, increased risk of headache and enlarged prostate, as well as with blood biomarkers of liver function. Heterozygosity was associated with higher height-adjusted forced expiratory volume in 1 s (FEV1) (β=19.36 mL, p=9.21×10−4) and FEV1/forced vital capacity (β=0.0031, p=1.22×10−5) in nonsmokers, whereas in smokers, this protective effect was abolished. Furthermore, we show for the first time that sex modifies the association of the Z allele on lung function.We conclude that Z allele heterozygosity and homozygosity exhibit opposing effects on lung function in the UK population, and that these associations are modified by smoking and sex. In exploratory analyses, heterozygosity for the Z allele also showed pleiotropic associations with nonrespiratory health-related traits and disease risk.
Highlights
Homozygosity for the SERPINA1 Z allele (rs28929474(T)) is the commonest cause of severe α1-antitrypsin deficiency (AATD) and is a well-established genetic risk factor for lung diseases such as chronic obstructive pulmonary disease (COPD)
The phenotypes most strongly associated with Z allele heterozygosity and Z allele homozygosity (FDR
Z allele homozygosity was associated with increased haemoglobin ( p=7.17×10−10), haematocrit ( p=6.17×10−8) and red blood cells ( p=5.91×10−5), as well as optic neuritis and pancreatitis. To extend these analyses to traits not previously available for the phenome-wide association studies (PheWASs), we investigated the effect of Z allele heterozygosity and homozygosity on 30 key blood biochemistry markers in UK Biobank data
Summary
Homozygosity for the SERPINA1 Z allele (rs28929474(T)) is the commonest cause of severe α1-antitrypsin deficiency (AATD) and is a well-established genetic risk factor for lung diseases such as chronic obstructive pulmonary disease (COPD). Some previous studies have sought to characterise the effect of Z allele heterozygosity on nonrespiratory traits, liver diseases [2,3,4,5,6]. These have often been carried out in small sample sizes and/or clinical subgroups. PheWASs test the association between genetic variants and a large number of phenotypic traits, including diseases and their subtypes, and potential intermediate phenotypes [7]. This differs from genome-wide association studies, which test a large number of variants across the genome for association with only one trait
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