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Allele-Specific Transcript Abundance: A Pilot Study in Healthy Centenarians.

ABSTRACT: The genetic basis of healthy aging and longevity remains largely unexplained. One hypothesis as to why long-lived individuals do not appear to have a lower number of common-complex disease variants, is that despite carrying risk variants, they express disease-linked alleles at a lower level than the wild-type alleles. Allele-specific abundance (ASA) is the different transcript abundance of the two haplotypes of a diploid individual. We sequenced the transcriptomes of four healthy centenarians and four mid-life controls. CIBERSORT was used to estimate blood cell fractions: neutrophils were the most abundant source of RNA, followed by CD8+ T cells, resting NK cells, and monocytes. ASA variants were more common in noncoding than coding regions. Centenarians and controls had a comparable distribution of ASA variants by predicted effect, and we did not observe an overall bias in expression toward major or minor alleles. Immune pathways were most highly represented among the gene set that showed ASA. Although we found evidence of ASA in disease-associated genes and transcription factors, we did not observe any differences in the pattern of expression between centenarians and controls in this small pilot study.

SUBMITTER: Tindale LC

PROVIDER: S-EPMC7243586 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Allele-Specific Transcript Abundance: A Pilot Study in Healthy Centenarians.

Tindale Lauren C LC Thiessen Nina N Leach Stephen S Brooks-Wilson Angela R AR

The journals of gerontology. Series A, Biological sciences and medical sciences 20200501 6

The genetic basis of healthy aging and longevity remains largely unexplained. One hypothesis as to why long-lived individuals do not appear to have a lower number of common-complex disease variants, is that despite carrying risk variants, they express disease-linked alleles at a lower level than the wild-type alleles. Allele-specific abundance (ASA) is the different transcript abundance of the two haplotypes of a diploid individual. We sequenced the transcriptomes of four healthy centenarians an ...[more]

PMID: 31504207

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Project description:Although the incidence of dementia increases exponentially with age, some individuals reach more than 100 years with fully retained cognitive abilities. To identify the characteristics associated with the escape or delay of cognitive decline, we initiated the 100-plus Study ( www.100plus.nl ). The 100-plus Study is an on-going prospective cohort study of Dutch centenarians who self-reported to be cognitively healthy, their first-degree family members and their respective partners. We collect demographics, life history, medical history, genealogy, neuropsychological data and blood samples. Centenarians are followed annually until death. PET-MRI scans and feces donation are optional. Almost 30% of the centenarians agreed to post-mortem brain donation. To date (September 2018), 332 centenarians were included in the study. We analyzed demographic statistics of the first 300 centenarians (25% males) included in the cohort. Centenarians came from higher socio-economic classes and had higher levels of education compared to their birth cohort; alcohol consumption of centenarians was similar, and most males smoked during their lifetime. At baseline, the centenarians had a median MMSE score of 25 points (IQR 22.0-27.5); most centenarians lived independently, retained hearing and vision abilities and were independently mobile. Mortality was associated with cognitive functioning: centenarians with a baseline MMSE score ≥ 26 points had a mortality percentage of 17% per annual year in the second year after baseline, while centenarians with a baseline MMSE score < 26 points had a mortality of 42% per annual year (p = 0.003). The cohort was 2.1-fold enriched with the neuroprotective APOE-ε2 allele relative to 60-80 year-old population controls (p = 4.8 × 10-7), APOE-ε3 was unchanged and the APOE-ε4 allele was 2.3-fold depleted (p = 6.3 × 10-7). Comprehensive characterization of the 100-plus cohort of cognitively healthy centenarians might reveal protective factors that explain the physiology of long-term preserved cognitive health.

Project description:ObjectivesThe fraction of the population that reaches the age of 100 years is growing. At this age, dementia incidence is high and cognitive functioning is highly variable across individuals. Normative data for neuropsychological tests are lacking in centenarians, which hampers the ability to evaluate their cognitive functioning for both research and clinical practice. Here, we generated norms for neuropsychological tests in a sample of cognitively healthy centenarians while taking sensory impairments into account.DesignCross-sectional cohort study.SettingCentenarians who participate in the prospective 100-plus Study.ParticipantsA total of 235 centenarians (71.5% female), who self-reported to be cognitively healthy, which was confirmed by an informant and a trained researcher.MeasurementsWe generated normative data for 15 cognitive tests, measuring global cognition (Mini-Mental State Examination [MMSE]), premorbid intelligence, attention, language, memory, executive function, and visuospatial function by multiple linear regressions and/or by reporting percentiles.ResultsNormative data for global cognition resulted in a mean MMSE score of 25.6 ± 3.1 (range = 17-30; interquartile range = 24-28). Vision problems and fatigue often complicated the ability to complete tests, and these problems explained 41% and 22% of the missing test scores, respectively. In contrast, hearing problems (4%) and task incomprehension (6%) rarely complicated test performance. While educational level was associated with performance on the majority of the tests, sex and age were only weakly associated with test performance.ConclusionsWe generated normative data for 15 common neuropsychological tests in a large sample of cognitively healthy centenarians, while taking age-related sensory impairments into consideration. These normative data allow the detection of deficits across a wide range of cognitive domains. Our results suggest that, next to education level, vision ability and the level of fatigue should be taken into account when evaluating cognitive functioning in centenarians. J Am Geriatr Soc 67:759-767, 2019.

Dataset Information

Allele-Specific Transcript Abundance: A Pilot Study in Healthy Centenarians.

Publications

Allele-Specific Transcript Abundance: A Pilot Study in Healthy Centenarians.

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