Hujoel, Margaux L. A.Gazal, StevenLoh, Po-RuPatterson, NickPrice, Alkes2022-06-062020-04-20Hujoel, Margaux L. A., Steven Gazal, Po-Ru Loh, Nick Patterson, Alkes Price. "Liability threshold modeling of case–control status and family history of disease increases association power." Nature Genetics 52, no. 5 (2020): 541-547. DOI: 10.1038/s41588-020-0613-61061-40361546-1718https://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37371894Family history of disease can provide valuable information in case-control association studies, but it is currently unclear how to best combine case-control status and family history of disease. We developed an association method based on posterior mean genetic liabilities under a liability threshold model, conditional on case-control status and family history (LT-FH). Analyzing 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 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 across all diseases (e.g. 690 loci for LT-FH vs. 423 for GWAS); relative improvements were similar when applying BOLT-LMM to GWAS, GWAX, LT-FH phenotypes. Thus, LT-FH greatly increases association power when family history of disease is available.en-USGeneticsJournal Article2022-06-0610.1038/s41588-020-0613-6