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Sökning: WFRF:(Pedersen Nancy L.) > (2010-2014)

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41.
  • Finkel, Deborah, et al. (författare)
  • Etiology of individual differences in human health and longevity
  • 2014
  • Ingår i: Annual Review of Gerontology and Geriatrics. - : Springer Publishing Company. - 0198-8794. ; 34:1, s. 189-227
  • Tidskriftsartikel (refereegranskat)abstract
    • In this chapter, we review of the field of gerontological genetics with respect to subjective and objective health, the role of stress on health, and finally frailty and longevity. For most indices of subjective and objective health, frailty, and longevity, genetic influences contribute only modestly to individual differences, wherein heritabilities are typically on the order of 35%–40%. Notable exceptions are the moderate to strong heritabilities for lipid measures and brain structure and function, with a remarkably increasing role of genetic influences for longevity with advancing age. Although candidate gene and genome-wide association studies (GWAS) studies have identified gene variants associated with many subjective and objective health traits, their effect sizes are typically relatively small, as expected for complex traits. There is some evidence for gene–environment interactions, and stress may be an important moderator of genetic variance for health. For example, carrying a risk genotype for cardiovascular disease (CVD) in the angiotensin converting enzyme gene (ACE) may predict stress responsivity and risk of cardiovascular-related diagnoses. Moreover, the gene coding for apolipoprotein E (APOE) may moderate responsiveness to stress evoking experiences, impact of physical exercise, and associate with sleep characteristics in those who develop cognitive impairments. For metabolic syndrome (MetS), encompassing the co-occurrence of obesity, hypertension, hypertriglyceridemia, and hyperinsulinemia, promising associations exist although no single genotype or any gene clusters have been consistently associated with MetS across populations, suggesting that complex gene–environment interactions must be understood before the use of genetic markers can be realized in clinical practice. Future investigations of subjective and objective health, frailty, and longevity are needed to further identify sources of genetic and environmental contributions—and their dynamics across adulthood—to advance understanding of aging processes, prevention, and intervention avenues, and ultimately successful aging.
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42.
  • Ganna, Andrea, 1985-, et al. (författare)
  • Genetic determinants of mortality : Can findings from genome-wide association studies explain variation in human mortality?
  • 2013
  • Ingår i: Human Genetics. - : Springer Science and Business Media LLC. - 0340-6717 .- 1432-1203. ; 132:5, s. 553-561
  • Tidskriftsartikel (refereegranskat)abstract
    • Twin studies have estimated the heritability of longevity to be approximately 20-30 %. Genome-wide association studies (GWAS) have revealed a large number of determinants of morbidity, but so far, no new polymorphisms have been discovered to be associated with longevity per se in GWAS. We aim to determine whether the genetic architecture of mortality can be explained by single nucleotide polymorphisms (SNPs) associated with common traits and diseases related to mortality. By extensive quality control of published GWAS we created a genetic score from 707 common SNPs associated with 125 diseases or risk factors related with overall mortality. We prospectively studied the association of the genetic score with: (1) time-to-death; (2) incidence of the first of nine major diseases (coronary heart disease, stroke, heart failure, diabetes, dementia, lung, breast, colon and prostate cancers) in two population-based cohorts of Dutch and Swedish individuals (N = 15,039; age range 47-99 years). During a median follow-up of 6.3 years (max 22.2 years), we observed 4,318 deaths and 2,132 incident disease events. The genetic score was significantly associated with time-to-death [hazard ratio (HR) per added risk allele = 1.003, P value = 0.006; HR 4th vs. 1st quartile = 1.103]. The association between the genetic score and incidence of major diseases was stronger (HR per added risk allele = 1.004, P value = 0.002; HR 4th vs. 1st quartile = 1.160). Associations were stronger for individuals dying at older ages. Our findings are compatible with the view of mortality as a complex and highly polygenetic trait, not easily explainable by common genetic variants related to diseases and physiological traits.
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43.
  • Ganna, Andrea, et al. (författare)
  • Large-scale Metabolomic Profiling Identifies Novel Biomarkers for Incident Coronary Heart Disease
  • 2014
  • Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 10:12, s. e1004801-
  • Tidskriftsartikel (refereegranskat)abstract
    • Analyses of circulating metabolites in large prospective epidemiological studies could lead to improved prediction and better biological understanding of coronary heart disease (CHD). We performed a mass spectrometry-based non-targeted metabolomics study for association with incident CHD events in 1,028 individuals (131 events; 10 y. median follow-up) with validation in 1,670 individuals (282 events; 3.9 y. median follow-up). Four metabolites were replicated and independent of main cardiovascular risk factors [lysophosphatidylcholine 18∶1 (hazard ratio [HR] per standard deviation [SD] increment = 0.77, P-value<0.001), lysophosphatidylcholine 18∶2 (HR = 0.81, P-value<0.001), monoglyceride 18∶2 (MG 18∶2; HR = 1.18, P-value = 0.011) and sphingomyelin 28∶1 (HR = 0.85, P-value = 0.015)]. Together they contributed to moderate improvements in discrimination and re-classification in addition to traditional risk factors (C-statistic: 0.76 vs. 0.75; NRI: 9.2%). MG 18∶2 was associated with CHD independently of triglycerides. Lysophosphatidylcholines were negatively associated with body mass index, C-reactive protein and with less evidence of subclinical cardiovascular disease in additional 970 participants; a reverse pattern was observed for MG 18∶2. MG 18∶2 showed an enrichment (P-value = 0.002) of significant associations with CHD-associated SNPs (P-value = 1.2×10-7 for association with rs964184 in the ZNF259/APOA5 region) and a weak, but positive causal effect (odds ratio = 1.05 per SD increment in MG 18∶2, P-value = 0.05) on CHD, as suggested by Mendelian randomization analysis. In conclusion, we identified four lipid-related metabolites with evidence for clinical utility, as well as a causal role in CHD development.
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44.
  • Ganna, Andrea, et al. (författare)
  • Multilocus Genetic Risk Scores for Coronary Heart Disease Prediction
  • 2013
  • Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - : Lippincott Williams & Wilkins. - 1079-5642 .- 1524-4636. ; 33:9, s. 2267-2272
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective-Current guidelines do not support the use of genetic profiles in risk assessment of coronary heart disease (CHD). However, new single nucleotide polymorphisms associated with CHD and intermediate cardiovascular traits have recently been discovered. We aimed to compare several multilocus genetic risk score (MGRS) in terms of association with CHD and to evaluate clinical use. Approach and Results-We investigated 6 Swedish prospective cohort studies with 10 612 participants free of CHD at baseline. We developed 1 overall MGRS based on 395 single nucleotide polymorphisms reported as being associated with cardiovascular traits, 1 CHD-specific MGRS, including 46 single nucleotide polymorphisms, and 6 trait-specific MGRS for each established CHD risk factors. Both the overall and the CHD-specific MGRS were significantly associated with CHD risk (781 incident events; hazard ratios for fourth versus first quartile, 1.54 and 1.52; P<0.001) and improved risk classification beyond established risk factors (net reclassification improvement, 4.2% and 4.9%; P=0.006 and 0.017). Discrimination improvement was modest (C-index improvement, 0.004). A polygene MGRS performed worse than the CHD-specific MGRS. We estimate that 1 additional CHD event for every 318 people screened at intermediate risk could be saved by measuring the CHD-specific genetic score in addition to the established risk factors. Conclusions-Our results indicate that genetic information could be of some clinical value for prediction of CHD, although further studies are needed to address aspects, such as feasibility, ethics, and cost efficiency of genetic profiling in the primary prevention setting.
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45.
  • Ganna, Andrea, et al. (författare)
  • Utilizing Twins as Controls for Non-Twin Case-Materials in Genome Wide Association Studies
  • 2013
  • Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:12, s. e83101-
  • Tidskriftsartikel (refereegranskat)abstract
    • Twin registries around the globe have collected DNA samples from large numbers of monozygotic and dizygotic twins. The twin sample collections are frequently used as controls in disease-specific studies together with non-twins. This approach is unbiased under the hypothesis that twins and singletons are comparable in terms of allele frequencies; i.e. there are no genetic variants associated with being a twin per se. To test this hypothesis we performed a genome-wide association study comparing the allele frequency of 572,352 single nucleotide polymorphisms (SNPs) in 1,413 monozygotic (MZ) and 5,451 dizygotic (DZ) twins with 3,720 healthy singletons. Twins and singletons have been genotyped using the same platform. SNPs showing association with being a twin at P-value < 1 × 10-5 were selected for replication analysis in 1,492 twins (463 MZ and 1,029 DZ) and 1,880 singletons from Finland. No SNPs reached genome-wide significance (P-value < 5 × 10-8) in the main analysis combining MZ and DZ twins. In a secondary analysis including only DZ twins two SNPs (rs2033541 close to ADAMTSL1 and rs4149283 close to ABCA1) were genome-wide significant after meta-analysis with the Finnish population. The estimated proportion of variance on the liability scale explained by all SNPs was 0.08 (P-value=0.003) when MZ and DZ were considered together and smaller for MZ (0.06, P-value=0.10) compared to DZ (0.09, P-value=0.003) when analyzed separately. In conclusion, twins and singletons can be used in genetic studies together with general population samples without introducing large bias. Further research is needed to explore genetic variances associated with DZ twinning.
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46.
  • Gatz, Margaret, et al. (författare)
  • Dementia : Genes, environments, interactions
  • 2014
  • Ingår i: Behavior genetics of cognition across the lifespan. - New York : Springer. - 9781461474470 - 9781461474463 ; , s. 201-231
  • Bokkapitel (refereegranskat)abstract
    • Dementia is an increasingly prevalent disorder as the world population ages, with Alzheimer disease the most common cause. Twin studies find concordance to be substantially higher among monozygotic as compared with dizygotic twin pairs. While a few genes have been identified that are responsible for early-onset Alzheimer disease, they account for well under 5 % of all cases. Among susceptibility genes for Alzheimer disease identified by association studies, population attributable fraction for the most prominent of these—apolipoprotein E—is estimated to be about 25 %, whereas other genes at best predict another 20 %. There are few strong environmental risk or protective factors, with vascular risks the best established, although with mechanisms still not fully understood. It seems likely that clusters of risk alleles, interactions between risk alleles and environmental exposures, and epigenetic mechanisms play a role in explaining Alzheimer disease, with different combinations of influences culminating in the observed pathophysiology. In particular, environmental exposures early in life could lead to deleterious changes in gene expression in late life.
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47.
  • Hallberg, Jenny, et al. (författare)
  • Genetic and environmental influence on lung function impairment in Swedish twins
  • 2010
  • Ingår i: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 11
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The understanding of the influence of smoking and sex on lung function and symptoms is important for understanding diseases such as COPD. The influence of both genes and environment on lung function, smoking behaviour and the presence of respiratory symptoms has previously been demonstrated for each of these separately. Hence, smoking can influence lung function by co-varying not only as an environmental factor, but also by shared genetic pathways. Therefore, the objective was to evaluate heritability for different aspects of lung function, and to investigate how the estimates are affected by adjustments for smoking and respiratory symptoms. Methods: The current study is based on a selected sample of adult twins from the Swedish Twin Registry. Pairs were selected based on background data on smoking and respiratory symptoms collected by telephone interview. Lung function was measured as FEV1, VC and DLco. Pack years were quantified, and quantitative genetic analysis was performed on lung function data adjusting stepwise for sex, pack years and respiratory symptoms. Results: Fully adjusted heritability for VC was 59% and did not differ by sex, with smoking and symptoms explaining only a small part of the total variance. Heritabilities for FEV1 and DLco were sex specific. Fully adjusted estimates were 10 and 15% in men and 46% and 39% in women, respectively. Adjustment for smoking and respiratory symptoms altered the estimates differently in men and women. For FEV1 and DLco, the variance explained by smoking and symptoms was larger in men. Further, smoking and symptoms explained genetic variance in women, but was primarily associated with shared environmental effects in men. Conclusion: Differences between men and women were found in how smoking and symptoms influence the variation in lung function. Pulmonary gas transfer variation related to the menstrual cycle has been shown before, and the findings regarding DLco in the present study indicates gender specific environmental susceptibility not shown before. As a consequence the results suggest that patients with lung diseases such as COPD could benefit from interventions that are sex specific.
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48.
  • Hassing, Linda B, et al. (författare)
  • Overweight in midlife is related to lower cognitive function later in life
  • 2010
  • Konferensbidrag (refereegranskat)abstract
    • Objectives: To examine the long-term effects of midlife overweight for cognitive abilities. The evidence is growing strong that overweight in midlife is related to increased dementia risk. Few studies have addressed the question if overweight affects cognitive abilities among those who do not develop dementia. In two studies we examined cognitive performance in two cohorts of people (young-old and old) in relation to self-reported Body Mass Index (BMI) in midlife. Methods: The participants are from the Swedish Twin Registry who participated in longitudinal studies on aging and cognition, the SATSA study (young-old cohort, 50 years and older) and the OCTO-Twin study (old cohort, 80 years and older) . BMI was reported in 1963 and cognitive abilities were examined 20- to 30-years later with five measurement occasions at 3-year intervals (SATSA) respectively 2-year intervals (OCTO-Twin). The cognitive abilities examined included tests of long-term memory, short-term memory, speed, verbal ability, spatial ability and a composite score representing general cognitive ability. Results: Multilevel modeling adjusting for twinship, demographic factors, cardiovascular diseases, and diabetes, showed that higher BMI in midlife predicted lower test performance 30 years later. Significant associations were found in all cognitive abilities. Although we found a significant cognitive decline across the five measurement occassions in both cohorts at the follow-up assessments, a higher midlife BMI was not associated with steeper decline in the old cohort, with the exception of verbal ability. This was, however, found for a measure of general cognitive ability and spatial ability in the young-old cohort.Conclusions: Our results indicate that midlife overweight is related to lower overall cognitive function in old age. The fact that BMI-related effects in slopes were only noted in some abilities in the young-old cohort suggests that the negative effect of overweight has an early onset.
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49.
  • Hemani, Gibran, et al. (författare)
  • Inference of the Genetic Architecture Underlying BMI and Height with the Use of 20,240 Sibling Pairs
  • 2013
  • Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 93:5, s. 865-875
  • Tidskriftsartikel (refereegranskat)abstract
    • Evidence that complex traits are highly polygenic has been presented by population-based genome-wide association studies (GWASs) through the identification of many significant variants, as well as by family-based de novo sequencing studies indicating that several traits have a large mutational target size. Here, using a third study design, we show results consistent with extreme polygenicity for body mass index (BMI) and height. On a sample of 20,240 siblings (from 9,570 nuclear families), we used a within-family method to obtain narrow-sense heritability estimates of 0.42 (SE = 0.17, p = 0.01) and 0.69 (SE = 0.14, p = 6 x 10(-7)) for BMI and height, respectively, after adjusting for covariates. The genomic inflation factors from locus-specific-linkage analysis were 1.69 (SE = 0.21, p = 0.04) for BMI and 2.18 (SE = 0.21, p = 2 x 10(-10)) for height. This inflation is free of confounding and congruent with polygenicity, consistent with observations of ever-increasing genomic-inflation factors from GWASs with large sample sizes, implying that those signals are due to true genetic signals across the genome rather than population stratification. We also demonstrate that the distribution of the observed test statistics is consistent with both rare and common variants underlying a polygenic architecture and that previous reports of linkage signals in complex traits are probably a consequence of polygenic architecture rather than the segregation of variants with large effects. The convergent empirical evidence from GWASs, de novo studies, and within-family segregation implies that family-based sequencing studies for complex traits require very large sample sizes because the effects of causal variants are small on average.
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50.
  • Hughes, Tiffany F, et al. (författare)
  • Midlife fruit and vegetable consumption and risk of dementia in later life in Swedish twins.
  • 2010
  • Ingår i: The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry. - 1545-7214 .- 1064-7481. ; 18:5, s. 413-20
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: Diet may be associated with risk of dementia and Alzheimer disease (AD). The authors examined the association between fruit and vegetable consumption in midlife and risk for all types of dementia and AD. METHODS: Participants were 3,779 members of the Swedish Twin Registry who completed a diet questionnaire approximately 30 years before cognitive screening and full clinical evaluation for dementia as part of the study of dementia in Swedish Twins (HARMONY) study. Among the participants, 355 twins were diagnosed with dementia. Among these, 81 twin pairs were discordant for dementia (50 discordant for AD). Data were analyzed with logistic regression for the entire sample using generalized estimating equations to adjust for relatedness of twins and with conditional logistic regression for the co-twin control design. RESULTS: In fully adjusted models, a medium or great proportion of fruits and vegetables in the diet, compared with no or small, was associated with a decreased risk of dementia and AD. This effect was observed among women and those with angina. Similar, but nonsignificant, odds ratios were found in the co-twin control analyses. CONCLUSION: The findings suggest that higher fruit and vegetable consumption may reduce the risk of dementia, especially among women and those with angina pectoris in midlife.
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