Variants associated with HHIP expression have sex-differential effects on lung function
Bibliographic record
Abstract
<ns4:p><ns4:bold>Background: </ns4:bold>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.</ns4:p><ns4:p> <ns4:bold>Methods:</ns4:bold> 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.</ns4:p><ns4:p> <ns4:bold>Results:</ns4:bold> Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P<5x10<ns4:sup>-8</ns4:sup>) interactions with sex on lung function, and 21 showed suggestive interactions (P<1x10<ns4:sup>-6</ns4:sup>). The strongest signal, from rs7697189 (chr4:145436894) on forced expiratory volume in 1 second (FEV<ns4:sub>1</ns4:sub>) (P=3.15x10<ns4:sup>-15</ns4:sup>), was replicated (P=0.016) in SpiroMeta. The C allele increased FEV<ns4:sub>1</ns4:sub> more in males (untransformed FEV<ns4:sub>1</ns4:sub> 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 (<ns4:italic>HHIP</ns4:italic>) gene and was previously associated with lung function and <ns4:italic>HHIP</ns4:italic> lung expression. We found <ns4:italic>HHIP</ns4:italic> expression was significantly different between the sexes (P=6.90x10<ns4:sup>-6</ns4:sup>), but we could not detect sex differential effects of rs7697189 on expression.</ns4:p><ns4:p> <ns4:bold>Conclusions:</ns4:bold> We identified a novel genotype-by-sex interaction at a putative enhancer region upstream of the <ns4:italic>HHIP</ns4:italic> gene. Establishing the mechanism by which <ns4:italic>HHIP</ns4:italic> 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.</ns4:p>
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.004 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".