Meta-analysis of genetic variants associated with human exceptional longevity

Despite evidence from family studies that there is a strong genetic influence upon exceptional longevity, relatively few genetic variants have been associated with this trait. One reason could be that many genes individually have such weak effects that they cannot meet standard thresholds of genome wide significance, but as a group in specific combinations of genetic variations, they can have a strong influence. Previously we reported that such genetic signatures of 281 genetic markers associated with about 130 genes can do a relatively good job of differentiating centenarians from non-centenarians particularly if the centenarians are 106 years and older. This would support our hypothesis that the genetic influence upon exceptional longevity increases with older and older (and rarer) ages. We investigated this list of markers using similar genetic data from 5 studies of centenarians from the USA, Europe and Japan. The results from the meta-analysis show that many of these variants are associated with survival to these extreme ages in other studies. Since many centenarians compress morbidity and disability towards the end of their lives, these results could point to biological pathways and therefore new therapeutics to increase years of healthy lives in the general population

Gender and sexual orientation differences in cognition across adulthood : age is kinder to women than to men regardless of sexual orientation

Despite some evidence of greater age-related deterioration of the brain in males than in females, gender differences in rates of cognitive aging have proved inconsistent. The present study employed web-based methodology to collect data from people aged 20-65 years (109,612 men; 88,509 women). As expected, men outperformed women on tests of mental rotation and line angle judgment, whereas women outperformed men on tests of category fluency and object location memory. Performance on all tests declined with age but significantly more so for men than for women. Heterosexuals of each gender generally outperformed bisexuals and homosexuals on tests where that gender was superior; however, there were no clear interactions between age and sexual orientation for either gender. At least for these particular tests from young adulthood to retirement, age is kinder to women than to men, but treats heterosexuals, bisexuals, and homosexuals just the same

Genome wide association and linkage analyses identified three loci-4q25, 17q23.2, and 10q11.21-associated with variation in leukocyte telomere length: the Long Life Family Study

Leukocyte telomere length is believed to measure cellular aging in humans, and short leukocyte telomere length is associated with increased risks of late onset diseases, including cardiovascular disease, dementia, etc. Many studies have shown that leukocyte telomere length is a heritable trait, and several candidate genes have been identified, including TERT, TERC, OBFC1, and CTC1. Unlike most studies that have focused on genetic causes of chronic diseases such as heart disease and diabetes in relation to leukocyte telomere length, the present study examined the genome to identify variants that may contribute to variation in leukocyte telomere length among families with exceptional longevity. From the genome wide association analysis in 4,289 LLFS participants, we identified a novel intergenic SNP rs7680468 located near PAPSS1 and DKK2 on 4q25 (p = 4.7E-8). From our linkage analysis, we identified two additional novel loci with HLOD scores exceeding three, including 4.77 for 17q23.2, and 4.36 for 10q11.21. These two loci harbor a number of novel candidate genes with SNPs, and our gene-wise association analysis identified multiple genes, including DCAF7, POLG2, CEP95, and SMURF2 at 17q23.2; and RASGEF1A, HNRNPF, ANF487, CSTF2T, and PRKG1 at 10q11.21. Among these genes, multiple SNPs were associated with leukocyte telomere length, but the strongest association was observed with one contiguous haplotype in CEP95 and SMURF2. We also show that three previously reported genes—TERC, MYNN, and OBFC1—were significantly associated with leukocyte telomere length at p(empirical) < 0.05

Clustering by genetic ancestry using genome-wide SNP data

<p>Abstract</p> <p>Background</p> <p>Population stratification can cause spurious associations in a genome-wide association study (GWAS), and occurs when differences in allele frequencies of single nucleotide polymorphisms (SNPs) are due to ancestral differences between cases and controls rather than the trait of interest. Principal components analysis (PCA) is the established approach to detect population substructure using genome-wide data and to adjust the genetic association for stratification by including the top principal components in the analysis. An alternative solution is genetic matching of cases and controls that requires, however, well defined population strata for appropriate selection of cases and controls.</p> <p>Results</p> <p>We developed a novel algorithm to cluster individuals into groups with similar ancestral backgrounds based on the principal components computed by PCA. We demonstrate the effectiveness of our algorithm in real and simulated data, and show that matching cases and controls using the clusters assigned by the algorithm substantially reduces population stratification bias. Through simulation we show that the power of our method is higher than adjustment for PCs in certain situations.</p> <p>Conclusions</p> <p>In addition to reducing population stratification bias and improving power, matching creates a clean dataset free of population stratification which can then be used to build prediction models without including variables to adjust for ancestry. The cluster assignments also allow for the estimation of genetic heterogeneity by examining cluster specific effects.</p

Humanistic psychotherapy research 1990-2015 : from methodological innovation to evidence-supported treatment outcomes and beyond

Over the past twenty five years, humanistic psychotherapy (HP) researchers have actively contributed to the development and implementation of innovative practice-informed research measures and coding systems. Qualitative and quantitative research findings, including meta-analyses, support the identification of HP approaches as evidence-based treatments for a variety of psychological conditions. Implications for future psychotherapy research, training and practice are discussed in terms of addressing the persistent disjunction between significant HP research productivity and relatively low support for HP approaches in university-based clinical training programs, funding agencies and government-supported clinical guidelines. Finally, specific recommendations are provided to further enhance and expand the impact of humanistic psychotherapy research for clinical training programs and the development of treatment guidelines

Cancer: Are offspring of long-lived siblings both robust and resilient?

Background: The mechanisms underlying clustering of longevity in families are unclear. We have previously shown a low cancer incidence in offspring of long-lived siblings, i.e. cancer robustness. Here we test whether such offspring are also more resilient in terms of survival after cancer diagnosis. Methods: Identification of offspring from long-lived families was undertaken in three nationwide, consecutive Danish studies (DOS, GeHA, LLFS). Cancer cases were identified through linkage with the Danish Cancer Registry. Each offspring cancer case was matched with two control cancer cases from the 5\ sex, year of diagnosis and cancer site. The main outcome was overall survival. Factors studied were sociodemographic, health-related and cancer-related. Survival analyses were performed using stratified Cox proportional hazards models based on the matching data. Results: Among the 5,377 offspring of the 634 families, 465 offspring of long-lived siblings with first primary cancer were included, along with 930 controls. Offspring of long-lived siblings had a significantly better survival than controls (HR=0.64 95\0.52-0.78]). The association attenuated only slightly after adjustment of marital status, education, Charlson Comorbidity Index, and number of prescribed drugs (HR=0.66 95\0.54-0.81]). Conclusion: Our results suggest that in addition to being more robust to cancer risk, offspring of long-lived siblings are also more resilient to cancer after its diagnosis and show better overall survival compared to individuals with cancer from general Danish population. Funding: The LLFS study is funded by the US National Institute on Aging / National Institutes of Health

A comparative analysis of body psychotherapy and dance movement psychotherapy from a European perspective

The role of embodiment within contemporary psychotherapy practice and its discussion are gathering momentum, and are part of a paradigm shift in psychotherapy in which theory and practice are being reformulated. Body psychotherapy (BP) and dance movement psychotherapy (DMP) are playing a leading role in these deliberations. Although these two professions have separate professional bodies, distinct theoretical grounding and clinical methodology, they both place enormous value on the central role of the body and its movement as indicators of relational problems, and as agents of therapeutic change. There are few authors comparing and contrasting BP and DMP although they have much in common as they are both embodied, enactive psychotherapies. However, neither their overlaps in theory, methodology and some of their clinical practice nor their distinct character has been sufficiently delineated. This article elucidates some similarities and differences in fundamental assumptions, compares and contrasts definitions and terms and considers common and contrasting theoretical perspectives, techniques and methods. It is expected that this will contribute to the ongoing discussion of the articulation of core characteristics in both professions and will facilitate a better understanding and collaboration between them

Imputation of missing genotypes: an empirical evaluation of IMPUTE

<p>Abstract</p> <p>Background</p> <p>Imputation of missing genotypes is becoming a very popular solution for synchronizing genotype data collected with different microarray platforms but the effect of ethnic background, subject ascertainment, and amount of missing data on the accuracy of imputation are not well understood.</p> <p>Results</p> <p>We evaluated the accuracy of the program IMPUTE to generate the genotype data of partially or fully untyped single nucleotide polymorphisms (SNPs). The program uses a model-based approach to imputation that reconstructs the genotype distribution given a set of referent haplotypes and the observed data, and uses this distribution to compute the marginal probability of each missing genotype for each individual subject that is used to impute the missing data. We assembled genome-wide data from five different studies and three different ethnic groups comprising Caucasians, African Americans and Asians. We randomly removed genotype data and then compared the observed genotypes with those generated by IMPUTE. Our analysis shows 97% median accuracy in Caucasian subjects when less than 10% of the SNPs are untyped and missing genotypes are accepted regardless of their posterior probability. The median accuracy increases to 99% when we require 0.95 minimum posterior probability for an imputed genotype to be acceptable. The accuracy decreases to 86% or 94% when subjects are African Americans or Asians. We propose a strategy to improve the accuracy by leveraging the level of admixture in African Americans.</p> <p>Conclusion</p> <p>Our analysis suggests that IMPUTE is very accurate in samples of Caucasians origin, it is slightly less accurate in samples of Asians background, but substantially less accurate in samples of admixed background such as African Americans. Sample size and ascertainment do not seem to affect the accuracy of imputation.</p

Association between late maternal age and age-related endophenotypes in the Long Life Family Study

Extended maternal age has been suggested as marker of delayed age-associated disabilities. We use the Long Life Family Study (LLFS) offspring generation to investigate the association between extended maternal age at last childbirth and healthy-aging endophenotypes. We hypothesize that women with extended maternal age at last childbirth will exhibit healthier endophenotype profiles compared to younger mothers. The association between maternal age and age-related endophenotypes previously derived in LLFS was assessed using Generalized Estimating Equations to adjust for relatedness. The quartiles of the maternal age at last childbirth were modeled as the independent variables. Univariate analyses tested the association between maternal age at last childbirth and age at clinical assessment, education, field center, Apolipoprotein E (APOE) genotype, depression, stress, smoking and successful pregnancies. Only the variables significantly associated in the univariate analyses were considered in secondary multivariate analyses. Univariate analyses showed that compared to older mothers (age at last birth ≥35), mothers 30 years old or younger at last childbirth are less educated (12 ± 3 years versus 13 ± 3 years) and have a higher frequency of smoking (9% versus 3% for maternal age ≥35). Results showed that older mothers (age at last birth ≥31–34 or ≥ 35) demonstrated significantly better cognitive profiles (p = 0.017 and p = 0.021 respectively) compared with mothers with last childbirth age ≤30. Later maternal age among women from long-life families is associated with a better cognitive profile, supporting the hypothesis that later age at childbirth may be a marker for healthy aging.</p

GWAS of longevity in CHARGE consortium confirms APOE and FOXO3 candidacy.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.The genetic contribution to longevity in humans has been estimated to range from 15% to 25%. Only two genes, APOE and FOXO3, have shown association with longevity in multiple independent studies.We conducted a meta-analysis of genome-wide association studies including 6,036 longevity cases, age ≥90 years, and 3,757 controls that died between ages 55 and 80 years. We additionally attempted to replicate earlier identified single nucleotide polymorphism (SNP) associations with longevity.In our meta-analysis, we found suggestive evidence for the association of SNPs near CADM2 (odds ratio [OR] = 0.81; p value = 9.66 × 10(-7)) and GRIK2 (odds ratio = 1.24; p value = 5.09 × 10(-8)) with longevity. When attempting to replicate findings earlier identified in genome-wide association studies, only the APOE locus consistently replicated. In an additional look-up of the candidate gene FOXO3, we found that an earlier identified variant shows a highly significant association with longevity when including published data with our meta-analysis (odds ratio = 1.17; p value = 1.85×10(-10)).We did not identify new genome-wide significant associations with longevity and did not replicate earlier findings except for APOE and FOXO3. Our inability to find new associations with survival to ages ≥90 years because longevity represents multiple complex traits with heterogeneous genetic underpinnings, or alternatively, that longevity may be regulated by rare variants that are not captured by standard genome-wide genotyping and imputation of common variants.Netherlands Organisation of Scientific Research NWO Investments 175.010.2005.011 911-03-012 Research Institute for Diseases in the Elderly 014-93-015 RIDE2 Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) 050-060-810 Erasmus Medical Center Erasmus University, Rotterdam Netherlands Organization for the Health Research and Development (ZonMw) Research Institute for Diseases in the Elderly (RIDE) Ministry of Education, Culture and Science Ministry for Health, Welfare and Sports European Commission (DG XII) Municipality of Rotterdam National Institutes of Health National Institute on Aging (NIA) R01 AG005407 R01 AR35582 R01 AR35583 R01 AR35584 R01 AG005394 R01 AG027574 R01 AG027576 AG023629 R01AG29451 U01AG009740 RC2 AG036495 RC4 AG039029 P30AG10161 R01AG17917 R01AG15819 R01AG30146 U01-AG023755 U19-AG023122 NHLBI HHSN 268201200036C HHSN268200800007C N01HC55222 N01HC85079 N01HC85080 N01HC85081 N01HC85082 N01HC85083 N01HC 85086 HL080295 HL087652 HL105756 National Institute of Neurological Disorders and Stroke (NINDS) National Center for Advancing Translational Sciences, CTSI UL1TR000124 National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) DK063491 National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) National Center for Research Resources (NCRR) NIH Roadmap for Medical Research U01 AR45580 U01 AR45614 U01 AR45632 U01 AR45647 U01 AR45654 U01 AR45583 U01 AG18197 U01-AG027810 UL1 RR024140 NIAMS R01-AR051124 RC2ARO58973 National Heart, Lung and Blood Institute's Framingham Heart Study N01-HC-25195 Affymetrix, Inc N02-HL-6-4278 Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine Boston Medical Center National Institute of Arthritis, Musculoskeletal and Skin Diseases NIA R01 AR/AG 41398 NIH N01-AG-12100 NIA Intramural Research Program Hjartavernd (the Icelandic Heart Association) Althingi (the Icelandic Parliament) Illinois Department of Public Health Translational Genomics Research Institute Italian Ministry of Health ICS110.1/RF97.71 U.S. National Institute on Aging 263 MD 9164 263 MD 821336 Intramural Research Program of the NIH, National Institute on Aging 1R01AG028321 1R01HL09257