Accounting for age of onset and family history improves power in genome-wide association studies
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Genome-wide association studies (GWASs) have revolutionized human genetics, allowing researchers to identify thousands of disease-related genes and possible drug targets. However, case-control status does not account for the fact that not all controls may have lived through their period of risk for the disorder of interest. This can be quantified by examining the age-of-onset distribution and the age of the controls or the age of onset for cases. The age-of-onset distribution may also depend on information such as sex and birth year. In addition, family history is not routinely included in the assessment of control status. Here, we present LT-FH++, an extension of the liability threshold model conditioned on family history (LT-FH), which jointly accounts for age of onset and sex as well as family history. Using simulations, we show that, when family history and the age-of-onset distribution are available, the proposed approach yields statistically significant power gains over LT-FH and large power gains over genome-wide association study by proxy (GWAX). We applied our method to four psychiatric disorders available in the iPSYCH data and to mortality in the UK Biobank and found 20 genome-wide significant associations with LT-FH++, compared to ten for LT-FH and eight for a standard case-control GWAS. As more genetic data with linked electronic health records become available to researchers, we expect methods that account for additional health information, such as LT-FH++, to become even more beneficial.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | American Journal of Human Genetics |
| Vol/bind | 109 |
| Udgave nummer | 3 |
| Sider (fra-til) | 417-432 |
| Antal sider | 16 |
| ISSN | 0002-9297 |
| DOI | |
| Status | Udgivet - 2022 |
Bibliografisk note
Funding Information:
J.C. has received honoraria for serving on the Scientific Advisory Board of Union Chimique Belge (UCB) Nordic and Eisai AB and for giving lectures for UCB Nordic and Eisai as well as travel funds from UCB Nordic and funding by the Novo Nordisk Foundation (grant number: NNF16OC0019126), the Central Denmark Region, and the Danish Epilepsy Association.
Funding Information:
We would like to thank Margaux Hujoel for useful discussions and allowing us to use the LT-FH++ name. We would like to thank Mark Daly for useful advice and helpful comments. F.P. and B.J.V. were supported by the Danish National Research Foundation (Niels Bohr Professorship to Prof. John McGrath). We also acknowledge the Lundbeck Foundation Initiative for Integrative Psychiatric Research , iPSYCH ( R102-A9118 , R155-2014-1724 , and R248-2017-2003 ). B.J.V. was also supported by a Lundbeck Foundation fellowship ( R335-2019-2339 ). High-performance computer capacity for handling and statistical analysis of iPSYCH data on the GenomeDK HPC facility was provided by the Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing, iSEQ, Aarhus University, Denmark (grant to A.D.B.). This research has been conducted with the UK Biobank Resource under application number 58024.
Funding Information:
We would like to thank Margaux Hujoel for useful discussions and allowing us to use the LT-FH++ name. We would like to thank Mark Daly for useful advice and helpful comments. F.P. and B.J.V. were supported by the Danish National Research Foundation (Niels Bohr Professorship to Prof. John McGrath). We also acknowledge the Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH (R102-A9118, R155-2014-1724, and R248-2017-2003). B.J.V. was also supported by a Lundbeck Foundation fellowship (R335-2019-2339). High-performance computer capacity for handling and statistical analysis of iPSYCH data on the GenomeDK HPC facility was provided by the Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing, iSEQ, Aarhus University, Denmark(grant to A.D.B.). This research has been conducted with the UK Biobank Resource under application number 58024. J.C. has received honoraria for serving on the Scientific Advisory Board of Union Chimique Belge (UCB) Nordic and Eisai AB and for giving lectures for UCB Nordic and Eisai as well as travel funds from UCB Nordic and funding by the Novo Nordisk Foundation (grant number: NNF16OC0019126), the Central Denmark Region, and the Danish Epilepsy Association.
Publisher Copyright:
© 2022 The Authors
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