Comment on the Relationship Between Common Variant Schizophrenia Liability and Number of Offspring in the UK Biobank
To the Editor: Escott-Price and colleagues recently reported an association between genetic liability for schizophrenia and number of children in the UK Biobank (1). They interpret this finding as consistent with sexual selection. However, the genetic data for the UK Biobank was released in two waves (May 2015 and July 2017) (2). Escott-Price and colleagues used the most recent genome-wide association study for schizophrenia, but the reported sample size suggests that data only from the first wave of the UK Biobank, comprising approximately 150,000 participants in total, were used (2). The first release of UK Biobank data was selected on the basis of smoking behavior (3) and, as we have demonstrated elsewhere (4), this can yield biased estimates in analyses.
We investigated a similar question to Escott-Price and colleagues (5), using different but related methods. Initially, when using the first release of UK Biobank data, we found results similar to those reported by Escott-Price and colleagues—a weak positive relationship between genetic liability for schizophrenia and number of children. However, given our concerns about conditioning on this subsample (with well-established associations between smoking and both schizophrenia risk and fertility) (6), we repeated our analyses in the full release. Strikingly, these results were quite different, with no clear evidence of a relationship between genetic liability for schizophrenia and number of children (5). The results for the two waves of UK Biobank data, and the full release, using our methods, are shown in Table 1.
| Genetic Liability for Schizophreniaa | Sample Size for Outcome Data | Number of Childrenb | ||
|---|---|---|---|---|
| β | 95% CI | p | ||
| First release | 90,058 to 94,792 | 0.012 | 0.00003, 0.023 | 0.05 |
| Second release | 228,863 to 240,966 | –0.001 | –0.008, 0.006 | 0.81 |
| Full UK Biobank data | 318,921 to 335,758 | 0.003 | –0.003, 0.009 | 0.39 |
TABLE 1. Estimates of the causal effect of genetic liability for schizophrenia on number of children using an inverse variance–weighted Mendelian randomization approach
Whether genetic risk for psychiatric disorders is associated with a reproductive advantage is an important question, as it may explain the persistence of these disorders despite deleterious effects. One possibility is that the discrepancy between our results and those of Escott-Price and colleagues is due to differences in the methodology we adopted. However, another is that the results reported by Escott-Price and colleagues are an artifact of conditioning on the first, selective release of UK Biobank data, which could be tested by repeating their exact analysis strategy in the full data release.
1 : The relationship between common variant schizophrenia liability and number of offspring in the UK Biobank. Am J Psychiatry (Epub ahead of print, Jan 4, 2019)Google Scholar
2 : The UK Biobank resource with deep phenotyping and genomic data. Nature 2018; 562:203–209Crossref, Medline, Google Scholar
3 : Novel insights into the genetics of smoking behaviour, lung function, and chronic obstructive pulmonary disease (UK BiLEVE): a genetic association study in UK Biobank. Lancet Respir Med 2015; 3:769–781Crossref, Medline, Google Scholar
4 : Collider scope: when selection bias can substantially influence observed associations. Int J Epidemiol 2018; 47:226–235Crossref, Medline, Google Scholar
5 : Schizophrenia risk and reproductive success: a Mendelian randomization study. Royal Society Open Science 2019Crossref, Medline, Google Scholar
6 : Causal effects of lifetime smoking on risk for depression and schizophrenia: evidence from a Mendelian randomisation study. bioRxiv 2018Google Scholar
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