Findings and insights from the genetic investigation of age of first reported occurrence for complex disorders in the UK Biobank and FinnGen

Abstract

Age of onset contains information on the timing of events relevant to disease etiology, but there has not been a systematic investigation of its heritability from GWAS data. Here, we characterize the genetic architecture of age of first occurrence and its genomic relationship with disease susceptibility for a wide range of complex disorders in the UK Biobank. For diseases with a sufficient sample size, we discover that age of first occurrence has non-trivial genetic contributions, some with specific genetic risk factors not associated with susceptibility to the disease. Through genetic correlation analysis, we show that an earlier health-event occurrence is correlated with a higher polygenic risk of disease susceptibility. An independent genetic investigation of the FinnGen cohort replicates the pattern of heritability and genetic correlation estimates. We then demonstrate that incorporating disease onset age with susceptibility may improve genetic risk prediction and stratification.

GWAS and ExWAS of blood mitochondrial DNA copy number identifies 71 loci and highlights a potential causal role in dementia

“…To assess evidence for a causal role of mtDNA-CN on MT disorder-related traits, we first defined a list of testable disease outcomes related to MT disorders. We cross-referenced a list of 36 clinical manifestations of MT disease to FinnGen consortium GWAS (release 4; November 30, 2020) traits ( Gorman et al, 2016 ; Feng, 2020 ). Among 2444 FinnGen traits, 10 overlapped with MT disease and had a case prevalence greater than 1% and were chosen for two-sample Mendelian randomization analyses.…”

“…First, genome-wide significant variants from the present European GWAS meta-analysis of mtDNA-CN were chosen (N=383,476). Second, we matched these variants to the FinnGen v4 GWAS datasets (Feng et al, 2020). Third, to enrich for variants that directly act through mitochondrial processes, we only retained those within 100kb of genes encoding for proteins that are expressed in mitochondria based on MitoCarta3 annotations (Rath et al, 2021).…”

Age-dependent impact of the major common genetic risk factor for COVID-19 on severity and mortality

“…While the main risk factor for severe outcomes is age, whose impact increases exponentially after age 60 (7), some younger individuals experience severe COVID-19 outcomes and death. The early onset of several common diseases such as breast cancers, myocardial infarction, and Alzheimer's disease, is disproportionally influenced by human genetic factors (10)(11)(12)(13) and this may also be the case for COVID-19. Several genome-wide association studies (GWAS) have identified multiple loci in the human genome associated with severity of COVID-19 (14)(15)(16)(17).…”

Understanding the comorbidity between posttraumatic stress severity and coronary artery disease using genome-wide information and electronic health records

“…However, we found the relationship between CAD and PTSD severity is affected by the timing of CAD onset. A recent study showed that, although earlier health-event occurrence is genetically correlated with a higher polygenic risk of disease susceptibility, age of first occurrence has specific genetic risk factors not associated with susceptibility to the disease 68 . With respect to outcomes related to the circulatory system, the genetic correlation between age of first occurrence and disease susceptibility was -0.56 68 , highlighting the presence of an independent genetic component between them.…”

“…A recent study showed that, although earlier health-event occurrence is genetically correlated with a higher polygenic risk of disease susceptibility, age of first occurrence has specific genetic risk factors not associated with susceptibility to the disease 68 . With respect to outcomes related to the circulatory system, the genetic correlation between age of first occurrence and disease susceptibility was -0.56 68 , highlighting the presence of an independent genetic component between them. Because of the effect of CAD onset on PTSD severity, we speculate that the association of higher CAD genetic liability with lower PCL-17 score could be due to the unaccounted effect of the genetic predisposition to cardiac disease onset among CAD cases.…”