A study of common Mendelian disease carriers across ageing British cohorts: meta-analyses reveal heterozygosity for alpha 1-antitrypsin deficiency increases respiratory capacity and height.

Journal of Medical Genetics
Teri-Louise NorthIan N M Day

Abstract

Several recessive Mendelian disorders are common in Europeans, including cystic fibrosis (CFTR), medium-chain-acyl-Co-A-dehydrogenase deficiency (ACADM), phenylketonuria (PAH) and alpha 1-antitrypsin deficiency (SERPINA1). In a multicohort study of >19,000 older individuals, we investigated the relevant phenotypes in heterozygotes for these genes: lung function (forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC)) for CFTR and SERPINA1; cognitive measures for ACADM and PAH; and physical capability for ACADM, PAH and SERPINA1. Findings were mostly negative but lung function in SERPINA1 (protease inhibitor (PI) Z allele, rs28929474) showed enhanced FEV1 and FVC (0.13 z-score increase in FEV1 (p=1.7 × 10(-5)) and 0.16 z-score increase in FVC (p=5.2 × 10(-8))) in PI-MZ individuals. Height adjustment (a known, strong correlate of FEV1 and FVC) revealed strong positive height associations of the Z allele (1.50 cm increase in height (p=3.6 × 10(-10))). The PI-MZ rare (2%) SNP effect is nearly four times greater than the 'top' common height SNP in HMGA2. However, height only partially attenuates the SERPINA1-FEV1 or FVC association (around 50%) and vice versa. Height SNP variants have recently been shown to be posi...Continue Reading

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Citations

Dec 23, 2016·Annals of the American Thoracic Society·Andrew Bush
Apr 2, 2021·The Application of Clinical Genetics·Susana Seixas, Patricia Isabel Marques
May 14, 2021·ERJ Open Research·Katherine A FawcettIan P Hall

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Methods Mentioned

BETA
Genotyping

Software Mentioned

Stata
RE
ELSA
Sweep
Haplotter
fastPHASE

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