| Title: | Variants associated with HHIP expression have sex-differential effects on lung function |
| Journal: | Wellcome Open Research |
| Published: | 1 Jun 2020 |
| DOI: | https://doi.org/10.12688/wellcomeopenres.15846.1 |
| URL: | https://wellcomeopenresearch.org/articles/5-111/v1/pdf |
Publication 9118
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Abstract
</p>
Background:</p>
Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females.</p>
</p>
</p>
Methods:</p>
We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent individuals from the SpiroMeta consortium.</p>
</p>
</p>
Results:</p>
Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P<5x10</p>
-8</p>
) interactions with sex on lung function, and 21 showed suggestive interactions (P<1x10</p>
-6</p>
). The strongest signal, from rs7697189 (chr4:145436894) on forced expiratory volume in 1 second (FEV</p>
1</p>
) (P=3.15x10</p>
-15</p>
), was replicated (P=0.016) in SpiroMeta. The C allele increased FEV</p>
1</p>
more in males (untransformed FEV</p>
1</p>
β=0.028 [SE 0.0022] litres) than females (β=0.009 [SE 0.0014] litres), and this effect was not accounted for by differential effects on height, smoking or pubertal age. rs7697189 resides upstream of the hedgehog-interacting protein (</p>
HHIP</p>
) gene and was previously associated with lung function and</p>
HHIP</p>
lung expression. We found</p>
HHIP</p>
expression was significantly different between the sexes (P=6.90x10</p>
-6</p>
), but we could not detect sex differential effects of rs7697189 on expression.</p>
</p>
</p>
Conclusions:</p>
We identified a novel genotype-by-sex interaction at a putative enhancer region upstream of the</p>
HHIP</p>
gene. Establishing the mechanism by which</p>
HHIP</p>
SNPs have different effects on lung function in males and females will be important for our understanding of lung health and diseases in both sexes.</p>
</p>
75 Authors
- Katherine A. Fawcett
- Ma'en Obeidat
- Carl Melbourne
- Nick Shrine
- Anna L. Guyatt
- Catherine John
- Jian'an Luan
- Anne Richmond
- Marta R. Moksnes
- Raquel Granell
- Stefan Weiss
- Medea Imboden
- Sebastian May-Wilson
- Pirro Hysi
- Thibaud S. Boutin
- Laura Portas
- Claudia Flexeder
- Sarah E. Harris
- Carol A. Wang
- Leo-Pekka Lyytikäinen
- Teemu Palviainen
- Rachel E. Foong
- Dirk Keidel
- Cosetta Minelli
- Claudia Langenberg
- Yohan Bossé
- Maarten Van den Berge
- Don D. Sin
- Ke Hao
- Archie Campbell
- David Porteous
- Sandosh Padmanabhan
- Blair H. Smith
- David M. Evans
- Sue Ring
- Arnulf Langhammer
- Kristian Hveem
- Cristen Willer
- Ralf Ewert
- Beate Stubbe
- Nicola Pirastu
- Lucija Klaric
- Peter K. Joshi
- Karina Patasova
- Mangino Massimo
- Ozren Polasek
- John M. Starr
- Stefan Karrasch
- Konstantin Strauch
- Thomas Meitinger
- Igor Rudan
- Taina Rantanen
- Kirsi Pietiläinen
- Mika Kähönen
- Olli T. Raitakari
- Graham L. Hall
- Peter D. Sly
- Craig E. Pennell
- Jaakko Kaprio
- Terho Lehtimäki
- Veronique Vitart
- Ian J. Deary
- Debbie Jarvis
- James F. Wilson
- Tim Spector
- Nicole Probst-Hensch
- Nicholas J. Wareham
- Henry Völzke
- John Henderson
- David P. Strachan
- Ben M. Brumpton
- Caroline Hayward
- Ian P. Hall
- Martin D. Tobin
- Louise V. Wain
1 Application
| Application ID | Title |
|---|---|
| 648 | Common and rare genetic variants in respiratory health: the UK Biobank Lung Exome Variant Evaluation (UK BiLEVE) consortium |
Enabling scientific discoveries that improve human health