Comment on the Relationship Between Common Variant Schizophrenia Liability and Number of Offspring in the UK Biobank
Publication: American Journal of Psychiatry
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 |
a
Schizophrenia genetic data are from the Psychiatric Genomics Consortium genome-wide association study (case subjects, N=35,123; control subjects, N=109,657; 101 single-nucleotide polymorphisms) (7).
b
Results were multiplied by 0.693 to represent the estimate per doubling in odds of the exposure.
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.
Acknowledgments
The authors are grateful to the participants of the UK Biobank as well as research staff who worked on data collection (UK Biobank application number 6326).
References
1.
Escott-Price V, Pardiñas AF, Santiago E, et al: 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)
2.
Bycroft C, Freeman C, Petkova D, et al: The UK Biobank resource with deep phenotyping and genomic data. Nature 2018; 562:203–209
3.
Wain LV, Shrine N, Miller S, et al: 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; 3:769–781
4.
Munafò MR, Tilling K, Taylor AE, et al: Collider scope: when selection bias can substantially influence observed associations. Int J Epidemiol 2018; 47:226–235
5.
Lawn RB, Sallis HM, Taylor AE, et al: Schizophrenia risk and reproductive success: a Mendelian randomization study. Royal Society Open Science 2019
6.
Wootton RE, Richmond RC, Stuijfzand BG, et al: Causal effects of lifetime smoking on risk for depression and schizophrenia: evidence from a Mendelian randomisation study. bioRxiv 2018
7.
Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 2014; 511:421–427
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Accepted: 25 February 2019
Published online: 1 July 2019
Published in print: July 01, 2019
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Competing Interests
The views expressed in this letter are those of the authors and not necessarily those of the National Health Service, the National Institute for Health Research, or the Department of Health and Social Care.
Funding Information
Supported by the Medical Research Council and the University of Bristol (grant number MC_UU_00011/7), the British Heart Foundation, Cancer Research UK, the Economic and Social Research Council, and the National Institute for Health Research under the auspices of the U.K. Clinical Research Collaboration.Drs. Taylor, Wootton, Penton-Voak, and Munafò are supported by the National Institute for Health Research Biomedical Research Center at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol. Dr. Taylor has received grant support from Pfizer. Dr. Davies has received funding from the Economics and Social Research Council via a Future Research Leaders grant (ES/N000757/1), grant support from Pfizer, and consultancy work from the CHDI Foundation. Dr. Hemani has received funding from the Wellcome Trust (208806/Z/17/Z). Dr. Fraser has received grant support from the U.K. Medical Research Council (MR/M009351/1). Dr. Munafò and Dr. Penton-Voak are codirectors of Jericoe, which produces software for the assessment and modification of emotion recognition. Dr. Munafò is a member of the U.K. Center for Tobacco and Alcohol Studies, is a consultant to Cambridge Cognition, and has received grant support from Pfizer and research support in kind from GlaxoSmithKline. Ms. Lawn’s studentship is funded by the Medical Research Council Integrative Epidemiology Unit at the University of Bristol. The other authors report no financial relationships with commercial interests.
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