Rxivist logo

Combining case-control status and family history of disease increases association power

By Margaux L.A. Hujoel, Steven Gazal, Po-Ru Loh, Nick Patterson, Alkes Price

Posted 02 Aug 2019
bioRxiv DOI: 10.1101/722645 (published DOI: 10.1038/s41588-020-0613-6)

Family history of disease can provide valuable information about an individual’s genetic liability for disease in case-control association studies, but it is currently unclear how to best combine case-control status and family history of disease. We developed a new association method based on posterior mean genetic liabilities under a liability threshold model, conditional on both case-control status and family history (LT-FH); association statistics are computed via linear regression of genotypes and posterior mean genetic liabilities, equivalent to a score test. We applied LT-FH to 12 diseases from the UK Biobank (average N=350K). We compared LT-FH to genome-wide association without using family history (GWAS) and a previous proxy-based method for incorporating family history (GWAX). LT-FH was +63% (s.e. 6%) more powerful than GWAS and +36% (s.e. 4%) more powerful than the trait-specific maximum of GWAS and GWAX, based on the number of independent genome-wide significant loci detected across all diseases (e.g. 690 independent loci for LT-FH vs. 423 for GWAS); the second best method was GWAX for lower-prevalence diseases and GWAS for higher-prevalence diseases, consistent with simulations. We also confirmed that LT-FH was well-calibrated (assessed via stratified LD score regression attenuation ratio), consistent with simulations. When using BOLT-LMM (instead of linear regression) to compute association statistics for all three methods (increasing the power of each method), LT-FH was +67% (s.e. 6%) more powerful than GWAS and +39% (s.e. 4%) more powerful than the trait-specific maximum of GWAS and GWAX. In summary, LT-FH greatly increases association power in case-control association studies when family history of disease is available.

Download data

  • Downloaded 1,353 times
  • Download rankings, all-time:
    • Site-wide: 18,786
    • In genetics: 820
  • Year to date:
    • Site-wide: 80,341
  • Since beginning of last month:
    • Site-wide: 126,213

Altmetric data

Downloads over time

Distribution of downloads per paper, site-wide