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A Genome-Wide Association Study of 2304 Extreme Longevity Cases Identifies Novel Longevity Variants.

ABSTRACT: We performed a genome-wide association study (GWAS) of human extreme longevity (EL), defined as surviving past the 99th survival percentile, by aggregating data from four centenarian studies. The combined data included 2304 EL cases and 5879 controls. The analysis identified a locus in CDKN2B-AS1 (rs6475609, p = 7.13 × 10^-8) that almost reached genome-wide significance and four additional loci that were suggestively significant. Among these, a novel rare variant (rs145265196) on chromosome 11 had much higher longevity allele frequencies in cases of Ashkenazi Jewish and Southern Italian ancestry compared to cases of other European ancestries. We also correlated EL-associated SNPs with serum proteins to link our findings to potential biological mechanisms that may be related to EL and are under genetic regulation. The findings from the proteomic analyses suggested that longevity-promoting alleles of significant genetic variants either provided EL cases with more youthful molecular profiles compared to controls or provided some form of protection from other illnesses, such as Alzheimer's disease, and disease progressions.

SUBMITTER: Bae H

PROVIDER: S-EPMC9820206 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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A Genome-Wide Association Study of 2304 Extreme Longevity Cases Identifies Novel Longevity Variants.

Bae Harold H Gurinovich Anastasia A Karagiannis Tanya T TT Song Zeyuan Z Leshchyk Anastasia A Li Mengze M Andersen Stacy L SL Arbeev Konstantin K Yashin Anatoliy A Zmuda Joseph J An Ping P Feitosa Mary M Giuliani Cristina C Franceschi Claudio C Garagnani Paolo P Mengel-From Jonas J Atzmon Gil G Barzilai Nir N Puca Annibale A Schork Nicholas J NJ Perls Thomas T TT Sebastiani Paola P

International journal of molecular sciences 20221221 1

We performed a genome-wide association study (GWAS) of human extreme longevity (EL), defined as surviving past the 99th survival percentile, by aggregating data from four centenarian studies. The combined data included 2304 EL cases and 5879 controls. The analysis identified a locus in CDKN2B-AS1 (rs6475609, <i>p</i> = 7.13 × 10<sup>-8</sup>) that almost reached genome-wide significance and four additional loci that were suggestively significant. Among these, a novel rare variant (rs145265196) o ...[more]

PMID: 36613555

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Project description:Childhood acute lymphoblastic leukemia (ALL) occurs more frequently in males. Reasons behind sex differences in childhood ALL risk are unknown. In the present genome-wide association study (GWAS), we explored the genetic basis of sex differences by comparing genotype frequencies between male and female cases in a case-only study to assess effect-modification by sex.The case-only design included 236 incident cases of childhood ALL consecutively recruited at the Texas Children's Cancer Center in Houston, Texas from 2007 to 2012. All cases were non-Hispanic whites, aged 1 to 10 years, and diagnosed with confirmed B-cell precursor ALL. Genotyping was performed using the Illumina HumanCoreExome BeadChip on the Illumina Infinium platform. Besides the top 100 statistically most significant results, results were also analyzed by the top 100 highest effect size with a nominal statistical significance (P <0.05).The statistically most significant sex-specific association (P = 4 × 10) was with the single nucleotide polymorphism (SNP) rs4813720 (RASSF2), an expression quantitative trait locus (eQTL) for RASSF2 in peripheral blood. rs4813720 is also a strong methylation QTL (meQTL) for a CpG site (cg22485289) within RASSF2 in pregnancy, at birth, childhood, and adolescence. cg22485289 is one of the hypomethylated CpG sites in ALL compared with pre-B cells. Two missense SNPs, rs12722042 and 12722039, in the HLA-DQA1 gene yielded the highest effect sizes (odds ratio [OR] ∼ 14; P <0.01) for sex-specific results. The HLA-DQA1 SNPs belong to DQA1*01 and confirmed the previously reported male-specific association with DQA1*01. This finding supports the proposed infection-related etiology in childhood ALL risk for males. Further analyses revealed that most SNPs (either direct effect or through linkage disequilibrium) were within active enhancers or active promoter regions and had regulatory effects on gene expression levels.Cumulative data suggested that RASSF2 rs4813720, which correlates with increased RASSF2 expression, may counteract the suppressor effect of estrogen-regulated miR-17-92 on RASSF2 resulting in protection in males. Given the amount of sex hormone-related mechanisms suggested by our findings, future studies should examine prenatal or early postnatal programming by sex hormones when hormone levels show a large variation.

Dataset Information

A Genome-Wide Association Study of 2304 Extreme Longevity Cases Identifies Novel Longevity Variants.

Publications

A Genome-Wide Association Study of 2304 Extreme Longevity Cases Identifies Novel Longevity Variants.

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