The relationship between 11 different polygenic longevity scores, parental lifespan, and disease diagnosis in the UK Biobank.

Large-scale genome-wide association studies (GWAS) strongly suggest that most traits and diseases have a polygenic component. This observation has motivated the development of disease-specific "polygenic scores (PGS)" that are weighted sums of the effects of disease-associated variants identified from GWAS that correlate with an individual's likelihood of expressing a specific phenotype. Although most GWAS have been pursued on disease traits, leading to the creation of refined "Polygenic Risk Scores" (PRS) that quantify risk to diseases, many GWAS have also been pursued on extreme human longevity, general fitness, health span, and other health-positive traits. These GWAS have discovered many genetic variants seemingly protective from disease and are often different from disease-associated variants (i.e., they are not just alternative alleles at disease-associated loci) and suggest that many health-positive traits also have a polygenic basis. This observation has led to an interest in "polygenic longevity scores (PLS)" that quantify the "risk" or genetic predisposition of an individual towards health. We derived 11 different PLS from 4 different available GWAS on lifespan and then investigated the properties of these PLS using data from the UK Biobank (UKB). Tests of association between the PLS and population structure, parental lifespan, and several cancerous and non-cancerous diseases, including death from COVID-19, were performed. Based on the results of our analyses, we argue that PLS are made up of variants not only robustly associated with parental lifespan, but that also contribute to the genetic architecture of disease susceptibility, morbidity, and mortality.

Don J ，Schork AJ ，Glusman G ，Rappaport N ，Cummings SR ，Duggan D ，Raju A ，Hellberg KG ，Gunn S ，Monti S ，Perls T ，Lapidus J ，Goetz LH ，Sebastiani P ，Schork NJ ... -  《-》

Trans-biobank analysis with 676,000 individuals elucidates the association of polygenic risk scores of complex traits with human lifespan.

Sakaue S ，Kanai M ，Karjalainen J ，Akiyama M ，Kurki M ，Matoba N ，Takahashi A ，Hirata M ，Kubo M ，Matsuda K ，Murakami Y ，FinnGen ，Daly MJ ，Kamatani Y ，Okada Y ... -  《-》

Human longevity: 25 genetic loci associated in 389,166 UK biobank participants.

Pilling LC ，Kuo CL ，Sicinski K ，Tamosauskaite J ，Kuchel GA ，Harries LW ，Herd P ，Wallace R ，Ferrucci L ，Melzer D ... -  《Aging-US》

Genome-wide association of polygenic risk extremes for Alzheimer's disease in the UK Biobank.

In just over a decade, advances in genome-wide association studies (GWAS) have offered an approach to stratify individuals based on genetic risk for disease. Using recent Alzheimer's disease (AD) GWAS results as the base data, we determined each individual's polygenic risk score (PRS) in the UK Biobank dataset. Using individuals within the extreme risk distribution, we performed a GWAS that is agnostic of AD phenotype and is instead based on known genetic risk for disease. To interpret the functions of the new risk factors, we conducted phenotype analyses, including a phenome-wide association study. We identified 246 loci surpassing the significance threshold of which 229 were not reported in the base AD GWAS. These include loci that showed suggestive levels of association in the base GWAS and loci not previously suspected to be associated with AD. Among these, there are loci, such as IL34 and KANSL1, that have since been shown to be associated with AD in recent studies. We also show highly significant genetic correlations with multiple health-related outcomes that provide insights into prodromal symptoms and comorbidities. This is the first study to utilize PRS as a phenotype-agnostic group classification in AD genetic studies. We identify potential new loci for AD and detail phenotypic analysis of these PRS extremes.

Gouveia C ，Gibbons E ，Dehghani N ，Eapen J ，Guerreiro R ，Bras J ... -  《Scientific Reports》

Genome-wide association study of multisite chronic pain in UK Biobank.

Johnston KJA ，Adams MJ ，Nicholl BI ，Ward J ，Strawbridge RJ ，Ferguson A ，McIntosh AM ，Bailey MES ，Smith DJ ... -  《PLoS Genetics》