Genetics of hand grip strength in mid to late life.
ABSTRACT: Hand grip strength (GS) is a predictor of mortality in older adults and is moderately to highly heritable, but no genetic variants have been consistently identified. We aimed to identify single nucleotide polymorphisms (SNPs) associated with GS in middle-aged to older adults using a genome-wide association study (GWAS). GS was measured using handheld dynamometry in community-dwelling men and women aged 55-85 from the Hunter Community Study (HCS, N = 2088) and the Sydney Memory and Ageing Study (Sydney MAS, N = 541). Genotyping was undertaken using Affymetrix microarrays with imputation to HapMap2. Analyses were performed using linear regression. No genome-wide significant results were observed in HCS nor were any of the top signals replicated in Sydney MAS. Gene-based analyses in HCS identified two significant genes (ZNF295, C2CD2), but these results were not replicated in Sydney MAS. One out of eight SNPs previously associated with GS, rs550942, located near the CNTF gene, was significantly associated with GS (p = 0.005) in the HCS cohort only. Study differences may explain the lack of consistent results between the studies, including the smaller sample size of the Sydney MAS cohort. Our modest sample size also had limited power to identify variants of small effect. Our results suggest that similar to various other complex traits, many genetic variants of small effect size may influence GS. Future GWAS using larger samples and consistent measures may prove more fruitful at identifying genetic contributors for GS in middle-aged to older adults.
Project description:Hippocampal atrophy is observed with ageing and age-related neurodegenerative disease. Identification of the genetic correlates of hippocampal volume (HV) and atrophy may assist in elucidating the mechanisms of ageing and age-related neurodegeneration. Using two community cohorts of older Caucasians we estimated the heritability of HV and examined associations of HV with previously identified single nucleotide polymorphisms (SNPs). In addition we undertook genome-association studies (GWAS) examining HV and HV atrophy. Participants were community-dwelling non-demented older adults from the longitudinal Sydney Memory and Ageing Study (Sydney MAS) (N = 498) and the Older Australian Twins Study (OATS) (N = 351) aged 65 and over. HV was measured using T1-weighted magnetic resonance images. Heritability of HV was estimated in OATS. Genome-wide genotyping was imputed using the 1K Genomes reference set. Associations with HV-candidate and Alzheimer's disease (AD)-related SNPs were investigated. A GWAS examining HV (in both cohorts) and an exploratory GWAS of HV atrophy over two years (in Sydney MAS only) were also undertaken. HV heritability was estimated at 62-65%. The previously identified GWAS HV SNP (rs6581612) and the candidate BDNF SNP (rs6265) were nominally significant (p = 0.047 and p = 0.041 respectively). No AD-related SNPs, including the APOE ?4 polymorphism, were significant. No significant results were observed for either of the GWAS undertaken. Despite our estimate of a high heritability of HV, our results are consistent with a highly polygenic model suggesting that SNPs identified from prior studies, including GWAS meta-analyses, can be difficult to replicate in smaller samples of older adults.
Project description:Unraveling the complexity of aging is crucial for understanding its mechanisms and its role as a risk factor for most chronic conditions. Advancements marked by genome-wide association studies (GWASs) have sparked interest in gene cataloguing in the context of aging and age-related conditions. Here, we used GWAS to explore whether single nucleotide polymorphisms (SNPs) were associated with functional and anthropometric parameters in a cohort of old community-dwellers enrolled in the ilSIRENTE study. Analyses were carried out in men and women aged 80+ years enrolled in the ilSIRENTE study (n?=?286) and replicated in the inCHIANTI study (n?=?1055). Genotyping was accomplished on Infinium Human610-QUAD version 1. In the ilSIRENTE population, genetic variants in ZNF295 and C2CD2 (rs928874 and rs1788355) on chromosome 21q22.3, were significantly associated with the 4-meter gait speed (rs928874, p?=?5.61?×?10-8; rs1788355, p?=?5.73?×?10-8). This association was not replicated in the inCHIANTI population. Our findings suggest that specific SNPs may be associated with a key measure of physical performance in older adults. GWASs using larger samples are needed to confirm these preliminary results to enhance our comprehension of complex age-associated phenomena.
Project description:Characterisation of grip strength (GS) using isometric dynamometry is central to the definition of sarcopenia. Determinants of low GS include: older age, shorter stature, low physical activity, poor nutrition, socioeconomic disadvantage and multimorbidity. Less is known about risk factors for accelerated loss of GS. We investigated determinants of level and 8-year loss of GS in 3703 men and women (aged 52-82 years) in the English Longitudinal Study of Ageing (ELSA). Four hundred and forty-one men and women (aged 59-71 years) who participated in a 10-year follow-up of the Hertfordshire Cohort Study (HCS) were used for replication. Variables were harmonised between cohorts. Change in GS was characterised using mixed-effects models in ELSA and a residual change approach in HCS and analysed for men and women combined. Men in ELSA and HCS had higher average levels of GS at baseline, and accelerated rates of loss, compared with women. In ELSA, older age, shorter stature and multimorbidity were correlated with lower level, and accelerated rate of loss, of GS in both sexes (accelerated loss of 0.04 (95% CI 0.00-0.08) standard deviation scores per additional morbidity after multivariable adjustment). Socioeconomic disadvantage, low level of physical activity and poorer self-reported health were also correlated with low GS level, but not loss rate, after multivariable adjustment. Analysis in HCS yielded similar results. Our results identify multimorbidity as a modifiable determinant of loss of muscle strength in later life, and raise the possibility that developmental influences may impact on rate of involutional decline in muscle strength.
Project description:Numerous host extrinsic and intrinsic factors affect the gut microbiota composition, but their cumulative effects do not sufficiently explain the variation in the microbiota, suggesting contributions of missing factors. The Japanese population possesses homogeneous genetic features suitable for genome-wide association study (GWAS). Here, we performed GWASs for human gut microbiota using 1068 healthy Japanese adults. To precisely evaluate genetic effects, we corrected for the impacts of numerous host extrinsic and demographic factors by introducing them as covariates, enabling us to discover five loci significantly associated with microbiome diversity measures: HS3ST4, C2CD2, 2p16.1, 10p15.1, and 18q12.2. Nevertheless, these five variants explain only a small fraction of the variation in the gut microbiota. We subsequently investigated the heritability of each of the 21 core genera and found that the abundances of six genera are heritable. We propose that the gut microbiota composition is affected by a highly polygenic architecture rather than several strongly associated variants in the Japanese population.
Project description:Coronary artery disease (CAD) is associated with cognitive decrements and risk of later dementia, but it is not known if shared genetic factors underlie this association. We tested whether polygenic risk for CAD was associated with cognitive ability in community-dwelling cohorts of middle-aged and older adults.Individuals from Generation Scotland: Scottish Family Health Study (GS:SFHS, N = 9865) and from the Lothian Birth Cohorts of 1921 (LBC1921, N?=?517) and 1936 (LBC1936, N?=?1005) provided cognitive data and genome-wide genotype data. Polygenic risk profile scores for CAD were calculated for all of the cohorts using the largest available genome-wide association studies (GWAS) data set, the CARDIoGRAM consortium (22?233 cases and 64?762 controls). Polygenic risk profile scores for CAD were then tested for their association with cognitive abilities in the presence and absence of manifest cardiovascular disease.A meta-analysis of all three cohorts showed a negative association between CAD polygenic risk and fluid cognitive ability (??=?-0.022, P?=?0.016), verbal intelligence (??=?-0.024, P?=?0.011) and memory (??=?-0.021, P?=?0.028).Increased polygenic risk for CAD is associated with lower cognitive ability in older adults. Common genetic variants may underlie some of the association between age-related cognitive decrements and the risk for CAD.
Project description:Cacao (Theobroma cacao) is a globally important crop, and its yield is severely restricted by disease. Two of the most damaging diseases, witches' broom disease (WBD) and frosty pod rot disease (FPRD), are caused by a pair of related fungi: Moniliophthora perniciosa and Moniliophthora roreri, respectively. Resistant cultivars are the most effective long-term strategy to address Moniliophthora diseases, but efficiently generating resistant and productive new cultivars will require robust methods for screening germplasm before field testing. Marker-assisted selection (MAS) and genomic selection (GS) provide two potential avenues for predicting the performance of new genotypes, potentially increasing the selection gain per unit time. To test the effectiveness of these two approaches, we performed a genome-wide association study (GWAS) and GS on three related populations of cacao in Ecuador genotyped with a 15K single nucleotide polymorphism (SNP) microarray for three measures of WBD infection (vegetative broom, cushion broom, and chirimoya pod), one of FPRD (monilia pod) and two productivity traits (total fresh weight of pods and % healthy pods produced). GWAS yielded several SNPs associated with disease resistance in each population, but none were significantly correlated with the same trait in other populations. Genomic selection, using one population as a training set to estimate the phenotypes of the remaining two (composed of different families), varied among traits, from a mean prediction accuracy of 0.46 (vegetative broom) to 0.15 (monilia pod), and varied between training populations. Simulations demonstrated that selecting seedlings using GWAS markers alone generates no improvement over selecting at random, but that GS improves the selection process significantly. Our results suggest that the GWAS markers discovered here are not sufficiently predictive across diverse germplasm to be useful for MAS, but that using all markers in a GS framework holds substantial promise in accelerating disease-resistance in cacao.
Project description:Apolipoprotein H (ApoH) is a multi-functional plasma glycoprotein that has been associated with negative health outcomes. ApoH levels have high heritability. We undertook a genome-wide association study of ApoH levels using the largest sample to date and replicated the results in an independent cohort (total N?=?1,255). In the discovery phase, a meta-analysis of two cohorts, the Sydney Memory and Ageing Study (Sydney MAS) and the Older Australian Twins Study (OATS) (n?=?942) revealed genome-wide significant results in or near the APOH gene on chromosome 17 (top SNP, rs7211380, p?=?1?×?10(-11)). The results were replicated in an independent cohort, the Hunter Community Study (p?<?0.002) (n?=?313). Conditional and joint analysis (COJO) confirmed the association of the chromosomal 17 region with ApoH levels. The set of independent SNPs identified by COJO explained 23% of the variance. The relationships between the top SNPs and cardiovascular/lipid/cognition measures and diabetes were assessed in Sydney MAS, with suggestive results observed for diabetes and cognitive performance. However, replication of these results in the smaller OATS cohort was not found. This work provides impetus for future research to better understand the contribution of genetics to ApoH levels and its possible impacts on health.
Project description:weak grip strength (GS) and chronic inflammation have been implicated in the aetiology of sarcopenia in older adults. Given the interrelationships between inflammatory biomarkers, a summary variable may provide better insight into the relationship between inflammation and muscle strength. This approach has not been investigated in very old adults (aged ?85) who are at highest risk of muscle weakness.we used mixed models to explore the prospective association between GS over 5 years in 845 participants in the Newcastle 85+ Study, and inflammatory components identified by principal component analysis (PCA). Cut-offs of ?27 kg (men) and ?16 (women) were used to define sub-cohorts with weak and normal GS at each assessment.PCA identified three components, which explained 70% of the total variance in seven baseline biomarkers. Basal interleukin-6 (IL-6) and tumour necrosis factor (TNF-?) had the highest loadings on Component 1; stimulated IL-6 and TNF-? and homocysteine the highest on Component 2; high-sensitivity C-reactive protein (hsCRP) loaded positively and albumin negatively to Component 3. In adjusted mixed models, only Component 3 was associated with GS. One SD increase of Component 3 was associated with a 0.41 kg lower GS initially (P = 0.03) in all participants, but not with GS decline over time. Similar conclusions held for those in the weak and normal GS sub-cohorts.an inflammatory profile including hsCRP and albumin was independently associated with baseline GS. Future studies linking inflammatory profiles and muscle strength are needed to corroborate these findings in older adults.
Project description:BACKGROUND:Evidence is scarce on the trend in prevalence of geriatric syndromes (GS). This study assesses how GS prevalence changes over time in Swedish older community-dwellers by socio-demography, and attempts to highlight factors that may contribute to explain the trend. METHODS:Data from Stockholm County Council Public Health Surveys in 2006, 2010 and 2014 were used. Old adults, aged 65-84?years, with measurements on GS items were identified. Thus, a total of 17,560 participants were selected in 2006 (n?=?6295), 2010 (n?=?6733) and 2014 (n?=?4532). Data on socio-demographics, lifestyles and health status were collected through questionnaires. GS was defined as having at least one of the following: insomnia, urinary incontinence, severe hearing/vision problem, functional decline, fall and depressive disorder. Logistic regression was performed to assess the prevalence trend as well as the change in the associations of sociodemographic factors, health behaviors and chronic disease with GS. RESULTS:From 2006 to 2014, the prevalence of GS remained stable (Ptrend?=?0.54). However, among old adults born outside Nordic countries, it increased significantly from 73.0% in 2006, 78.0% in 2010 to 83.0% in 2014 (Ptrend?<?0.001). Furthermore, the association with GS became stronger for born outside Nordic counties (Ptrend?<?0.001) and weaker for sedentary lifestyles (Ptrend?=?0.004), whereas the association did not change for other sociodemographic factors, health behaviors and chronic disease (all Ptrend?>?0.05). CONCLUSIONS:At population level, GS prevalence remained stable at a high level among Swedish old community-dwellers. There are noteworthy differences in GS trend between population groups, in particular to the detriment of older adults born outside Nordic countries.
Project description:Soil salinity is a growing problem in world production agriculture. Continued improvement in crop salt tolerance will require the implementation of innovative breeding strategies such as marker-assisted selection (MAS) and genomic selection (GS). Genetic analyses for yield and vigor traits under salt stress in alfalfa breeding populations with three different phenotypic datasets was assessed. Genotype-by-sequencing (GBS) developed markers with allele dosage and phenotypic data were analyzed by genome-wide association studies (GWAS) and GS using different models. GWAS identified 27 single nucleotide polymorphism (SNP) markers associated with salt tolerance. Mapping SNPs markers against the Medicago truncatula reference genome revealed several putative candidate genes based on their roles in response to salt stress. Additionally, eight GS models were used to estimate breeding values of the training population under salt stress. Highest prediction accuracies and root mean square errors were used to determine the best prediction model. The machine learning methods (support vector machine and random forest) performance best with the prediction accuracy of 0.793 for yield. The marker loci and candidate genes identified, along with optimized GS prediction models, were shown to be useful in improvement of alfalfa with enhanced salt tolerance. DNA markers and the outcome of the GS will be made available to the alfalfa breeding community in efforts to accelerate genetic gains, in the development of biotic stress tolerant and more productive modern-day alfalfa cultivars.