Common genetic associations between age-related diseases

Dönertaş, Handan Melike; Fabian, Daniel K.; Fuentealba, Matías; Partridge, Linda; Thornton, Janet M.

doi:10.1038/s43587-021-00051-5

Cited by 65 publications

(27 citation statements)

References 76 publications

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“…The remaining two loci— HYAL2 , 3p21.31, P (FE) = 5.24 × 10 −3 , rs709210; and PDE4B , 1p31.3, P (FE) = 2.94 × 10 −4 , rs6695557 (Supplementary Data 12 )—were replicated at 7.14 × 10 −3 level. In addition to the 6p21.32 ( HLA-DRA , rs9270599), two of the identified loci: at 8p21.1 (near SCARA3 ), and 2q37.1 (near ATG16L1 ) have been reported for AD ( SCARA3 35 , ATG16L1 21 , 32 , 36 ), and GIT traits ( SCARA3 : gastric or stomach ulcer 37 , ATG16L1 : IBD 38 , ulcerative colitis and Crohn’s disease 33 , 39 ). Supplementary Data 13 presents 24 independent SNPs, at 21 genomic loci, reaching genome-wide suggestive association ( P meta-analysis < 1 × 10 −5 ) for AD and PUD.…”

Section: Resultsmentioning

confidence: 99%

A large-scale genome-wide cross-trait analysis reveals shared genetic architecture between Alzheimer’s disease and gastrointestinal tract disorders

et al. 2022

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Consistent with the concept of the gut-brain phenomenon, observational studies suggest a relationship between Alzheimer’s disease (AD) and gastrointestinal tract (GIT) disorders; however, their underlying mechanisms remain unclear. Here, we analyse several genome-wide association studies (GWAS) summary statistics (N = 34,652–456,327), to assess the relationship of AD with GIT disorders. Findings reveal a positive significant genetic overlap and correlation between AD and gastroesophageal reflux disease (GERD), peptic ulcer disease (PUD), gastritis-duodenitis, irritable bowel syndrome and diverticulosis, but not inflammatory bowel disease. Cross-trait meta-analysis identifies several loci (Pmeta-analysis < 5 × 10−8) shared by AD and GIT disorders (GERD and PUD) including PDE4B, BRINP3, ATG16L1, SEMA3F, HLA-DRA, SCARA3, MTSS2, PHB, and TOMM40. Colocalization and gene-based analyses reinforce these loci. Pathway-based analyses demonstrate significant enrichment of lipid metabolism, autoimmunity, lipase inhibitors, PD-1 signalling, and statin mechanisms, among others, for AD and GIT traits. Our findings provide genetic insights into the gut-brain relationship, implicating shared but non-causal genetic susceptibility of GIT disorders with AD’s risk. Genes and biological pathways identified are potential targets for further investigation in AD, GIT disorders, and their comorbidity.

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Section: Resultsmentioning

confidence: 99%

A large-scale genome-wide cross-trait analysis reveals shared genetic architecture between Alzheimer’s disease and gastrointestinal tract disorders

et al. 2022

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“…Approximately 20% of white Europeans are homozygous for deletion of the FUT2 functional secretor allele (rs601338, Trp154Ter), leading to truncation and inactivation of the enzyme and non-secretion of the blood group antigens 60 . The FUT2 deletion has been associated with cholestatic and gastrointestinal conditions [61][62][63] . This led us to explore the biologically informed hypothesis that FUT2 secretor status modifies the effect of blood group antigen expression on protein levels, serving as an example of long-range gene-by-gene interaction.…”

Section: Abo Blood Group and Fut2 Secretor Epistasis Effectsmentioning

confidence: 99%

Genetic regulation of the human plasma proteome in 54,306 UK Biobank participants

Sun

Chiou

Traylor

et al. 2022

Preprint

103

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The UK Biobank Pharma Proteomics Project (UKB-PPP) is a collaboration between the UK Biobank (UKB) and thirteen biopharmaceutical companies characterising the plasma proteomic profiles of 54,306 UKB participants. Here, we describe results from the first phase of UKB-PPP, including protein quantitative trait loci (pQTL) mapping of 1,463 proteins that identifies 10,248 primary genetic associations, of which 85% are newly discovered. We also identify independent secondary associations in 92% of cis and 29% of trans loci, expanding the catalogue of genetic instruments for downstream analyses. The study provides an updated characterisation of the genetic architecture of the plasma proteome, leveraging population-scale proteomics to provide novel, extensive insights into trans pQTLs across multiple biological domains. We highlight genetic influences on ligand-receptor interactions and pathway perturbations across a diverse collection of cytokines and complement proteins, and illustrate long-range epistatic effects of ABO blood group and FUT2 secretor status on proteins with gastrointestinal tissue-enriched expression. We demonstrate the utility of these data for drug target discovery by extending the genetic proxied effect of PCSK9 levels on lipid concentrations, cardio- and cerebro-vascular diseases, and additionally disentangle specific genes and proteins perturbed at COVID-19 susceptibility loci. This public-private partnership provides the scientific community with an open-access proteomics resource of unprecedented breadth and depth to help elucidate biological mechanisms underlying genetic discoveries and accelerate the development of novel biomarkers and therapeutics.

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“…The potential for indirect fitness impacts throughout adulthood, as well as nonzero selection at postreproductive ages, may provide additional insight into the age profiles of disease expression. Selection for postreproductive survival should alter expectations of deleterious allele frequencies based on mutation accumulation or antagonistic pleiotropy and of disease age-at-onset profiles ( 20 , 83 ). Recent attempts at uncovering signals of viability selection for deleterious late-acting alleles in humans found very few common variants (only 2 of a possible 8 million), suggesting that nonzero purifying selection has weeded out many late-acting harmful alleles ( 84 ); our model suggests a plausible mechanism.…”

Section: Discussionmentioning

confidence: 99%

The importance of elders: Extending Hamilton’s force of selection to include intergenerational transfers

Davison

Gurven

2022

Proc. Natl. Acad. Sci. U.S.A.

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In classical evolutionary models, the force of natural selection diminishes with age toward zero by last reproduction. However, intergenerational resource transfers and other late-life contributions in social species may select for postreproductive longevity. We present a formal framework for estimating indirect fitness contributions via production transfers in a skills-intensive foraging niche, reflecting kinship and cooperation among group members. Among contemporary human hunter-gatherers and horticulturalists, indirect fitness contributions from transfers exceed direct reproductive contributions from before menopause until ages when surpluses end, around the modal age of adult death (∼70 y). Under reasonable assumptions, these benefits are the equivalent to having up to several more offspring after age 50. Despite early independence, minimal production surplus, and a shorter lifespan, chimpanzees could theoretically make indirect contributions if they adopted reliable food-sharing practices. Our results for chimpanzees hypothetically adopting hunter-gatherer subsistence suggest that a skills-intensive foraging ecology with late independence and late peak production could select for human-like life histories via positive feedback between longevity and late-life transfers. In contrast, life history changes preceding subsistence shifts would not favor further life extension or subsistence shifts. Our results formalize the theory that longevity can be favored under socioecological conditions characterized by parental and alloparental care funded through transfers of mid- to late-life production surpluses. We also extend our analysis beyond food transfers to illustrate the potential for indirect fitness contributions from pedagogy, or information transfers. While we focus mostly on humans, our approach is adaptable to any context or species where transfers can affect fitness.

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Common genetic associations between age-related diseases

Cited by 65 publications

References 76 publications

A large-scale genome-wide cross-trait analysis reveals shared genetic architecture between Alzheimer’s disease and gastrointestinal tract disorders

A large-scale genome-wide cross-trait analysis reveals shared genetic architecture between Alzheimer’s disease and gastrointestinal tract disorders

Genetic regulation of the human plasma proteome in 54,306 UK Biobank participants

The importance of elders: Extending Hamilton’s force of selection to include intergenerational transfers

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