During normal ageing, the gradual loss of telomeric DNA in dividing somatic cells can contribute to replicative senescence, apoptosis, or neoplastic transformation. In the genetic disorder ...dyskeratosis congenita, telomere shortening is accelerated, and patients have premature onset of many age-related diseases and early death. We aimed to assess an association between telomere length and mortality in 143 normal unrelated individuals over the age of 60 years. Those with shorter telomeres in blood DNA had poorer survival, attributable in part to a 3·18-fold higher mortality rate from heart disease (95% CI 1·36–7·45, p=0·0079), and an 8·54-fold higher mortality rate from infectious disease (1·52–47·9, p=0·015). These results lend support to the hypothesis that telomere shortening in human beings contributes to mortality in many age-related diseases.
Alzheimer's disease (AD) is the most common cause of dementia and AD risk clusters within families. Part of the familial aggregation of AD is accounted for by excess maternal vs. paternal ...inheritance, a pattern consistent with mitochondrial inheritance. The role of specific mitochondrial DNA (mtDNA) variants and haplogroups in AD risk is uncertain.
We determined the complete mitochondrial genome sequence of 1007 participants in the Cache County Study on Memory in Aging, a population-based prospective cohort study of dementia in northern Utah. AD diagnoses were made with a multi-stage protocol that included clinical examination and review by a panel of clinical experts. We used TreeScanning, a statistically robust approach based on haplotype networks, to analyze the mtDNA sequence data. Participants with major mitochondrial haplotypes H6A1A and H6A1B showed a reduced risk of AD (p=0.017, corrected for multiple comparisons). The protective haplotypes were defined by three variants: m.3915G>A, m.4727A>G, and m.9380G>A. These three variants characterize two different major haplogroups. Together m.4727A>G and m.9380G>A define H6A1, and it has been suggested m.3915G>A defines H6A. Additional variants differentiate H6A1A and H6A1B; however, none of these variants had a significant relationship with AD case-control status.
Our findings provide evidence of a reduced risk of AD for individuals with mtDNA haplotypes H6A1A and H6A1B. These findings are the results of the largest study to date with complete mtDNA genome sequence data, yet the functional significance of the associated haplotypes remains unknown and replication in others studies is necessary.
Ageing may be due to mutation accumulation across the lifespan, leading to tissue dysfunction, disease, and death. We tested whether germline autosomal mutation rates in young adults predict their ...remaining survival, and, for women, their reproductive lifespans. Age-adjusted mutation rates (AAMRs) in 61 women and 61 men from the Utah CEPH (Centre d'Etude du Polymorphisme Humain) families were determined. Age at death, cause of death, all-site cancer incidence, and reproductive histories were provided by the Utah Population Database, Utah Cancer Registry, and Utah Genetic Reference Project. Higher AAMRs were significantly associated with higher all-cause mortality in both sexes combined. Subjects in the top quartile of AAMRs experienced more than twice the mortality of bottom quartile subjects (hazard ratio HR, 2.07; 95% confidence interval CI, 1.21-3.56; p = 0.008; median survival difference = 4.7 years). Fertility analyses were restricted to women whose age at last birth (ALB) was ≥ 30 years, the age when fertility begins to decline. Women with higher AAMRs had significantly fewer live births and a younger ALB. Adult germline mutation accumulation rates are established in adolescence, and later menarche in women is associated with delayed mutation accumulation. We conclude that germline mutation rates in healthy young adults may provide a measure of both reproductive and systemic ageing. Puberty may induce the establishment of adult mutation accumulation rates, just when DNA repair systems begin their lifelong decline.
Although there is abundant evidence that human longevity is heritable, efforts to map loci responsible for variation in human lifespan have had limited success.
We identified individuals from a large ...multigenerational population database (the Utah Population Database) who exhibited high levels of both familial longevity and individual longevity. This selection identified 325 related "affected individuals", defined as those in the top quartile for both excess longevity (EL = observed lifespan - expected lifespan) and familial excess longevity (FEL = weighted average EL across all relatives). A whole-genome scan for genetic linkage was performed on this sample using a panel of 1100 microsatellite markers. A strongly suggestive peak (Z = 4.2, Monte Carlo-adjusted p-value 0.09) was observed in the vicinity of D3S3547 on chromosome 3p24.1, at a point nearly identical to that reported recently by an independent team of researchers from Harvard Medical School (HMS). Meta-analysis of linkage scores on 3p from the two studies produced a minimum nominal p-value of 1.005×10(-9) at 55 cM. Other potentially noteworthy peaks in our data occur on 18q23-24, 8q23, and 17q21. Meta-analysis results from combined UPDB and HMS data yielded additional support, but not formal replication, for linkage on 8q, 9q, and 17q.
Corroboration of the linkage of exceptional longevity to 3p22-24 greatly strengthens the case that genes in this region affect variation in longevity and suggest, therefore, an important role in the regulation of human lifespan. Future efforts should include intensive study of the 3p22-24 region.
Summary
We investigated the hypothesis that gene expression profiles in cultured cell lines from adults, aged 57–97 years, contain information about the biological age and potential longevity of the ...donors. We studied 104 unrelated grandparents from 31 Utah CEU (Centre d’Etude du Polymorphisme Humain – Utah) families, for whom lymphoblastoid cell lines were established in the 1980s. Combining publicly available gene expression data from these cell lines, and survival data from the Utah Population Database, we tested the relationship between expression of 2151 always‐expressed genes, age, and survival of the donors. Approximately 16% of 2151 expression levels were associated with donor age: 10% decreased in expression with age, and 6% increased with age. Cell division cycle 42 (CDC42) and CORO1A exhibited strong associations both with age at draw and survival after draw (multiple comparisons‐adjusted Monte Carlo P‐value < 0.05). In general, gene expressions that increased with age were associated with increased mortality. Gene expressions that decreased with age were generally associated with reduced mortality. A multivariate estimate of biological age modeled from expression data was dominated by CDC42 expression, and was a significant predictor of survival after blood draw. A multivariate model of survival as a function of gene expression was dominated by CORO1A expression. This model accounted for approximately 23% of the variation in survival among the CEU grandparents. Some expression levels were negligibly associated with age in this cross‐sectional dataset, but strongly associated with inter‐individual differences in survival. These observations may lead to new insights regarding the genetic contribution to exceptional longevity.
Developmental dysplasia of the hip (DDH) is a common birth defect and is thought to have genetic contributions to the phenotype. It is likely that DDH is genetically heterogeneous with environmental ...modifiers. The Utah Population Database (UPDB) is a computerized integration of pedigrees, vital statistics, and medical records representing over 6 million individuals, and is a unique resource providing the ability to search for familial factors beyond the nuclear family, decreasing the effect of a shared environment. The purpose of this study is to assess the degree of relationship between individuals with DDH.
Datasets were created from UPDB statewide birth certificates and from the University of Utah Health Sciences Center enterprise data warehouse using records for DDH and linked to the UPDB. Controls for the dataset were selected that matched cases on birth year and sex and 10 controls were selected per case. Statistics computed for each family were the number of descendants, the observed number of affected, the expected number of affected, P value, familial standardize incidence ratio, relative risks (RRs), and standard error. A kinship analysis tool was used to find pedigrees with excess DDH.
The combined data resulted in 1649 distinct individuals with DDH. RR was significantly increased in first-degree relatives (RR=12.1; P<0.000001), siblings (RR=11.9; P<0.000001) and first cousins (RR=1.7; P=0.04). A total of 468 families were identified with at least 5 affected individuals in a family. These results were then filtered to only contain families that had a P value of less than 0.01. This resulted in 141 founders with anywhere between 4 and 30 affected living descendants with a P value of less than 0.01 with family sizes ranging from 594 to 44,819 descendants. A total of 28 founders had a familial standardize incidence ratio of greater than 5.0.
These data suggest a genetic contribution to DDH with a 12-fold increase in risk for first-degree relatives. Better phenotypic characterization and classification will be critical for future genetic analyses.
Probabilistic record linkage is a method commonly used to determine whether demographic records refer to the same person. The Fellegi–Sunter method is a probabilistic approach that uses field weights ...based on log likelihood ratios to determine record similarity. This paper introduces an extension of the Fellegi–Sunter method that incorporates approximate field comparators in the calculation of field weights. The data warehouse of a large academic medical center was used as a case study. The approximate comparator extension was compared with the Fellegi–Sunter method in its ability to find duplicate records previously identified in the data warehouse using different demographic fields and matching cutoffs. The approximate comparator extension misclassified 25% fewer pairs and had a larger Welch’s T statistic than the Fellegi–Sunter method for all field sets and matching cutoffs. The accuracy gain provided by the approximate comparator extension grew as less information was provided and as the matching cutoff increased. Given the ubiquity of linkage in both clinical and research settings, the incremental improvement of the extension has the potential to make a considerable impact.
To identify factors associated with spontaneous preterm birth and to estimate the risk of its recurrence for the second through fourth births among women in Utah who had a first and any subsequent ...birth between 1989 and 2001, using a retrospective cohort study design.
Utah state birth records were reviewed to identify women with a first live birth and at least one subsequent live birth from 1989 to 2001. Recurrence risks for spontaneous preterm birth were calculated for first through fourth births. Then all parties (1-12) and multiple maternal risk factors were used to estimate recurrence risks for pre-term birth outcomes by multinomial regression. Recurrence risks for early and late spontaneous preterm birth were calculated. Recurrence also was evaluated as the fraction attributable to previous spontaneous preterm birth. Using the identified factors, the sample was divided and the model was estimated for a subset of births (1989-1999); its predictive value was tested on the remaining births (2000-2001).
Women who experienced a spontaneous preterm birth before 34 weeks of gestation in their first or second live birth had the highest rate of recurrence. Spontaneous preterm birth before 34 weeks was the highest risk factor for recurrence of early spontaneous preterm birth (relative risk 13.56, 95% confidence interval 11.5-16.0), and, in general, risks were highest for recurrences of same gestational age outcomes.
A history of a live spontaneous birth before 34 weeks of gestation is a strong predictor of subsequent spontaneous preterm birth. A model of clinical risk factors may be used to identify women at increased risk for recurrent spontaneous preterm birth.
The mitochondria are essential organelles and are the location of cellular respiration, which is responsible for the majority of ATP production. Each cell contains multiple mitochondria, and each ...mitochondrion contains multiple copies of its own circular genome. The ratio of mitochondrial genomes to nuclear genomes is referred to as mitochondrial copy number. Decreases in mitochondrial copy number are known to occur in many tissues as people age, and in certain diseases. The regulation of mitochondrial copy number by nuclear genes has been studied extensively. While mitochondrial variation has been associated with longevity and some of the diseases known to have reduced mitochondrial copy number, the role that the mitochondrial genome itself has in regulating mitochondrial copy number remains poorly understood.
We analyzed the complete mitochondrial genomes from 1007 individuals randomly selected from the Cache County Study on Memory Health and Aging utilizing the inferred evolutionary history of the mitochondrial haplotypes present in our dataset to identify sequence variation and mitochondrial haplotypes associated with changes in mitochondrial copy number. Three variants belonging to mitochondrial haplogroups U5A1 and T2 were significantly associated with higher mitochondrial copy number in our dataset.
We identified three variants associated with higher mitochondrial copy number and suggest several hypotheses for how these variants influence mitochondrial copy number by interacting with known regulators of mitochondrial copy number. Our results are the first to report sequence variation in the mitochondrial genome that causes changes in mitochondrial copy number. The identification of these variants that increase mtDNA copy number has important implications in understanding the pathological processes that underlie these phenotypes.
PDF
