2022
DOI: 10.1016/j.ajhg.2022.01.009
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Accounting for age of onset and family history improves power in genome-wide association studies

Abstract: Genome-wide association studies (GWASs) have revolutionized human genetics, allowing researchers to identify thousands of diseaserelated 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… Show more

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Cited by 22 publications
(33 citation statements)
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“…A striking exception is MTAG.FamHist, which preserves specificity. This extends previous observations that careful methods can exploit family history to improve genetic studies 43,44,55 . However, MTAG is highly sensitive to input phenotype selection, and therefore requires extensive domain knowledge, just like previous approaches including combining multiple depression measures 13 and GWAS by proxy 43 .…”
Section: Discussionsupporting
confidence: 86%
“…A striking exception is MTAG.FamHist, which preserves specificity. This extends previous observations that careful methods can exploit family history to improve genetic studies 43,44,55 . However, MTAG is highly sensitive to input phenotype selection, and therefore requires extensive domain knowledge, just like previous approaches including combining multiple depression measures 13 and GWAS by proxy 43 .…”
Section: Discussionsupporting
confidence: 86%
“…Such a scenario was demonstrated by our interaction model in the simulations. In addition, LT-FH has been extended to LT-FH ++ that adopts an age-dependent liability threshold model, which accounts for disease age of onset in addition to family history [ 17 ].…”
Section: Discussionmentioning
confidence: 99%
“…Multimodal approaches to risk prediction, exemplified by recent applications of machine learning (Koutsouleris et al, 2021; Rosen et al, 2021), can increase prognostic capacity by integrating clinical, environmental, and biological markers of risk. Ultimately, prognoses for the rapidity of illness progression could be further refined by integrating characteristics of the first identifiable symptom with other risk factors such as familial history and polygenic scores (Pedersen et al, 2021). Until these approaches are implemented and accessible to all, simple associations between early symptoms and the rapidity of illness progression can help tailor the intensity and timing of early interventions in at-risk individuals.…”
Section: Discussionmentioning
confidence: 99%