Dataset Information

Whole-Exome Sequencing of an Exceptional Longevity Cohort.

ABSTRACT: Centenarians represent a unique cohort to study the genetic basis for longevity and factors determining the risk of neurodegenerative disorders, including Alzheimer's disease (AD). The estimated genetic contribution to longevity is highest in centenarians and super-cententenarians, but few genetic variants have been shown to clearly impact this phenotype. While the genetic risk for AD and other dementias is now well understood, the frequency of known dementia risk variants in centenarians is not fully characterized. To address these questions, we performed whole-exome sequencing on 100 individuals of 98-108 years age in search of genes with large effect sizes towards the exceptional aging phenotype. Overall, we were unable to identify a rare protein-altering variant or individual genes with an increased burden of rare variants associated with exceptional longevity. Gene burden analysis revealed three genes of nominal statistical significance associated with extreme aging, including LYST, MDN1, and RBMXL1. Several genes with variants conferring an increased risk for AD and other dementias were identified, including TREM2, EPHA1, ABCA7, PLD3, MAPT, and NOTCH3. Larger centenarian studies will be required to further elucidate the genetic basis for longevity, and factors conferring protection against age-dependent neurodegenerative syndromes.

SUBMITTER: Nygaard HB

PROVIDER: S-EPMC6696723 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Whole-Exome Sequencing of an Exceptional Longevity Cohort.

Nygaard Haakon B HB Erson-Omay E Zeynep EZ Wu Xiujuan X Kent Brianne A BA Bernales Cecily Q CQ Evans Daniel M DM Farrer Matthew J MJ Vilariño-Güell Carles C Strittmatter Stephen M SM

The journals of gerontology. Series A, Biological sciences and medical sciences 20190801 9

Centenarians represent a unique cohort to study the genetic basis for longevity and factors determining the risk of neurodegenerative disorders, including Alzheimer's disease (AD). The estimated genetic contribution to longevity is highest in centenarians and super-cententenarians, but few genetic variants have been shown to clearly impact this phenotype. While the genetic risk for AD and other dementias is now well understood, the frequency of known dementia risk variants in centenarians is not ...[more]

PMID: 29750252

Similar Datasets

Project description:BACKGROUND AND OBJECTIVES:Steroid-resistant nephrotic syndrome overwhelmingly progresses to ESRD. More than 30 monogenic genes have been identified to cause steroid-resistant nephrotic syndrome. We previously detected causative mutations using targeted panel sequencing in 30% of patients with steroid-resistant nephrotic syndrome. Panel sequencing has a number of limitations when compared with whole exome sequencing. We employed whole exome sequencing to detect monogenic causes of steroid-resistant nephrotic syndrome in an international cohort of 300 families. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:Three hundred thirty-five individuals with steroid-resistant nephrotic syndrome from 300 families were recruited from April of 1998 to June of 2016. Age of onset was restricted to <25 years of age. Exome data were evaluated for 33 known monogenic steroid-resistant nephrotic syndrome genes. RESULTS:In 74 of 300 families (25%), we identified a causative mutation in one of 20 genes known to cause steroid-resistant nephrotic syndrome. In 11 families (3.7%), we detected a mutation in a gene that causes a phenocopy of steroid-resistant nephrotic syndrome. This is consistent with our previously published identification of mutations using a panel approach. We detected a causative mutation in a known steroid-resistant nephrotic syndrome gene in 38% of consanguineous families and in 13% of nonconsanguineous families, and 48% of children with congenital nephrotic syndrome. A total of 68 different mutations were detected in 20 of 33 steroid-resistant nephrotic syndrome genes. Fifteen of these mutations were novel. NPHS1, PLCE1, NPHS2, and SMARCAL1 were the most common genes in which we detected a mutation. In another 28% of families, we detected mutations in one or more candidate genes for steroid-resistant nephrotic syndrome. CONCLUSIONS:Whole exome sequencing is a sensitive approach toward diagnosis of monogenic causes of steroid-resistant nephrotic syndrome. A molecular genetic diagnosis of steroid-resistant nephrotic syndrome may have important consequences for the management of treatment and kidney transplantation in steroid-resistant nephrotic syndrome.

Dataset Information

Whole-Exome Sequencing of an Exceptional Longevity Cohort.

Publications

Whole-Exome Sequencing of an Exceptional Longevity Cohort.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets