Genome-Wide Epistatic Network Analyses of Semantic Fluency in Older Adults.

Semantic fluency impairment has been attributed to a wide range of neurocognitive and psychiatric conditions, especially in the older population. Moderate heritability estimates on semantic fluency were obtained from both twin and family-based studies suggesting genetic contributions to the observed variation across individuals. Currently, effort in identifying the genetic variants underlying the heritability estimates for this complex trait remains scarce. Using the semantic fluency scale and genome-wide SNP genotype data from the Long Life Family Study (LLFS), we performed a genome-wide association study (GWAS) and epistasis network analysis on semantic fluency in 2289 individuals aged over 60 years from the American LLFS cohorts and replicated the findings in 1129 individuals aged over 50 years from the Danish LLFS cohort. In the GWAS, two SNPs with genome-wide significance (rs3749683, p = 2.52 × 10-8; rs880179, p = 4.83 × 10-8) mapped to the CMYAS gene on chromosome 5 were detected. The epistasis network analysis identified five modules as significant (4.16 × 10-5 < p < 7.35 × 10-3), of which two were replicated (p < 3.10 × 10-3). These two modules revealed significant enrichment of tissue-specific gene expression in brain tissues and high enrichment of GWAS catalog traits, e.g., obesity-related traits, blood pressure, chronotype, sleep duration, and brain structure, that have been reported to associate with verbal performance in epidemiological studies. Our results suggest high tissue specificity of genetic regulation of gene expression in brain tissues with epistatic SNP networks functioning jointly in modifying individual verbal ability and cognitive performance.

Ensemble-based classification using microRNA expression identifies a breast cancer patient subgroup with an ultralow long-term risk of metastases.

BACKGROUND: Current clinical markers overestimate the recurrence risk in many lymph node negative (LNN) breast cancer (BC) patients such that a majority of these low-risk patients unnecessarily receive systemic treatments. We tested if differential microRNA expression in primary tumors allows reliable identification of indolent LNN BC patients to provide an improved classification tool for overtreatment reduction in this patient group. METHODS: We collected freshly frozen primary tumors of 80 LNN BC patients with recurrence and 80 recurrence-free patients (mean follow-up: 20.9 years). The study comprises solely systemically untreated patients to exclude that administered treatments confound the metastasis status. Samples were pairwise matched for clinical-pathological characteristics to minimize dependence of current markers. Patients were classified into risk-subgroups according to the differential microRNA expression of their tumors via classification model building with cross-validation using seven classification methods and a voting scheme. The methodology was validated using available data of two independent cohorts (n = 123, n = 339). RESULTS: Of the 80 indolent patients (who would all likely receive systemic treatments today) our ultralow-risk classifier correctly identified 37 while keeping a sensitivity of 100% in the recurrence group. Multivariable logistic regression analysis confirmed independence of voting results from current clinical markers. Application of the method in two validation cohorts confirmed successful classification of ultralow-risk BC patients with significantly prolonged recurrence-free survival. CONCLUSION: Profiles of differential microRNAs expression can identify LNN BC patients who could spare systemic treatments demanded by currently applied classifications. However, further validation studies are required for clinical implementation of the applied methodology.

Cognitively high-performing oldest old individuals are physically active and have strong motor skills-A study of the Danish 1905 and 1915 birth cohorts.

Preserving cognitive function with age or super-aging greatly contributes to successful aging. Super-aging nonagenarians born in Denmark in either year 1905 or 1915 were classified as Cognitively High-Performing Oldest Old individuals with a five item cognitive composite score, equivalent to or better than mean middle-aged subjects. Cognitively high-performers were more physically active and had a better physical performance on e.g., Activity of Daily Living (p-value < 0.01), gait speed (p-value < 0.01) and grip strength (p-value < 0.05) compared with age-matched peers. Cognitive high-performing was also linked to lower depression symptomatology. When comparing super-agers with semi super-agers classified by Mini Mental State Examination > 27, super-agers were still more physically active and had a better physical performance (p-value < 0.05). Results suggests that physical activity is a lifestyle factor strongly associated with both semi and full cognitive super-aging.

Transcription Factor Regulation of Gene Expression Network by ZNF385D and HAND2 in Carotid Atherosclerosis.

Carotid intima-media thickness (CIMT) is a surrogate indicator for atherosclerosis and has been shown to predict cardiovascular risk in multiple large studies. Identification of molecular markers for carotid atheroma plaque formation can be critical for early intervention and prevention of atherosclerosis. This study performed transcription factor (TF) network analysis of global gene expression data focusing on two TF genes, ZNF385D and HAND2, whose polymorphisms have been recently reported to show association with CIMT. Genome-wide gene expression data were measured from pieces of carotid endarterectomy collected from 34 hypertensive patients (atheroma plaque of stages IV and above according to the Stary classification) each paired with one sample of distant macroscopically intact tissue (stages I and II). Transcriptional regulation networks or the regulons were reconstructed for ZNF385D (5644 target genes) and HAND2 (781 target genes) using network inference. Their association with the progression of carotid atheroma was examined using gene-set enrichment analysis with extremely high statistical significance for regulons of both ZNF385D and HAND2 (p < 6.95 × 10-7) suggesting the involvement of expression quantitative loci (eQTL). Functional annotation of the regulon genes found heavy involvement in the immune system's response to inflammation and infection in the development of atherosclerosis. Detailed examination of the regulation and correlation patterns suggests that activities of the two TF genes could have high clinical and interventional impacts on impairing carotid atheroma plaque formation and preventing carotid atherosclerosis.

Genetic associations with longevity are on average stronger in females than in males.

It is long observed that females tend to live longer than males in nearly every country. However, the underlying mechanism remains elusive. In this study, we discovered that genetic associations with longevity are on average stronger in females than in males through bio-demographic analyses of genome-wide association studies (GWAS) dataset of 2178 centenarians and 2299 middle-age controls of Chinese Longitudinal Healthy Longevity Study (CLHLS). This discovery is replicated across North and South regions of China, and is further confirmed by North-South discovery/replication analyses of different and independent datasets of Chinese healthy aging candidate genes with CLHLS participants who are not in CLHLS GWAS, including 2972 centenarians and 1992 middle-age controls. Our polygenic risk score analyses of eight exclusive groups of sex-specific genes, analyses of sex-specific and not-sex-specific individual genes, and Genome-wide Complex Trait Analysis using all SNPs all reconfirm that genetic associations with longevity are on average stronger in females than in males. Our discovery/replication analyses are based on genetic datasets of in total 5150 centenarians and compatible middle-age controls, which comprises the worldwide largest sample of centenarians. The present study's findings may partially explain the well-known male-female health-survival paradox and suggest that genetic variants may be associated with different reactions between males and females to the same vaccine, drug treatment and/or nutritional intervention. Thus, our findings provide evidence to steer away from traditional view that "one-size-fits-all" for clinical interventions, and to consider sex differences for improving healthcare efficiency. We suggest future investigations focusing on effects of interactions between sex-specific genetic variants and environment on longevity as well as biological function.

Long-term Impact of Prenatal Famine on Differential DNA Methylation of Genes in the Serotonin Receptor Signalling Pathway in Adults.

The correlation of early life adversity with adulthood psychopathology has already been revealed by epidemiological studies. To find the biological mechanisms underlying the cross-talk between prenatal adversity and mental health, molecular genetic studies have been performed using animal models of prenatal undernutrition and stress, reporting altered expression of serotonin receptors which modulate the release of many neurotransmitters that regulate a broad range of physiological functions including psychopathology. Unfortunately, no such study has been possible on humans due to ethical reasons. Using the Chinese Famine of 1959-1961 as a natural experiment, we investigated DNA methylation patterns in genes of the serotonin receptor signaling pathway in the whole blood of adults born during the famine. A significant pattern of reduced DNA methylation was observed in sex combined samples (p value, 0.022). In a sex-stratified analysis, the pattern was only significant in females (p-value, 0.019) but not in males. We further tested the DNA methylation patterns specifically in HTR1A, HTR2A and the X-linked HTR2C and found reduced DNA methylation in females for HTR2A (p-value 0.033) and HTR2C (p-value 0.014) but not in males. Overall, this study reveals altered epigenetic regulation of the serotonin receptor signaling pathway in association with prenatal adversity in humans providing novel epigenetic evidence in support of neurodevelopmental origin of psychiatric disorders.

Identification of key DNA methylation changes on fasting plasma glucose: a genome-wide DNA methylation analysis in Chinese monozygotic twins.

BACKGROUND: Elevated fasting plasma glucose (FPG) levels can increase morbidity and mortality even when it is below the diagnostic threshold of type 2 diabetes mellitus (T2DM). We conducted a genome-wide DNA methylation analysis to detect DNA methylation (DNAm) variants potentially related to FPG in Chinese monozygotic twins. METHODS: Genome-wide DNA methylation profiling in whole blood of twins was performed using Reduced Representation Bisulfite Sequencing (RRBS), yielding 551,447 raw CpGs. Association between DNAm of single CpG and FPG was tested using a generalized estimation equation. Differentially methylated regions (DMRs) were identified using comb-P approach. ICE FALCON method was utilized to perform the causal inference. Candidate CpGs were quantified and validated using Sequenom MassARRAY platform in a community population. Weighted gene co-expression network analysis (WGCNA) was conducted using gene expression data from twins. RESULTS: The mean age of 52 twin pairs was 52 years (SD: 7). The relationship between DNAm of 142 CpGs and FPG reached the genome-wide significance level. Thirty-two DMRs within 24 genes were identified, including TLCD1, MRPS31P5, CASZ1, and CXADRP3. The causal relationship of top CpGs mapped to TLCD1, MZF1, PTPRN2, SLC6A18, ASTN2, IQCA1, GRIN1, and PDE2A genes with FPG were further identified using ICE FALCON method. Pathways potentially related to FPG were also identified, such as phospholipid-hydroperoxide glutathione peroxidase activity and mitogen-activated protein kinase p38 binding. Three CpGs mapped to SLC6A18 gene were validated in a community population, with a hypermethylated direction in diabetic patients. The expression levels of 18 genes (including SLC6A18 and TLCD1) were positively correlated with FPG levels. CONCLUSIONS: We detect many DNAm variants that may be associated with FPG in whole blood, particularly the loci within SLC6A18 gene. Our findings provide important reference for the epigenetic regulation of elevated FPG levels and diabetes.

Postoperative prognostic nomogram for adult grade II/III astrocytoma in the Chinese Han population.

Background: Prognostic models of glioma have been the focus of many studies. However, most of them are based on Western populations. Additionally, because of the complexity of healthcare data in China, it is important to select a suitable model based on existing clinical data. This study aimed to develop and independently validate a nomogram for predicting the overall survival (OS) with newly diagnosed grade II/III astrocytoma after surgery. Methods: Data of 472 patients with astrocytoma (grades II-III) were collected from Qilu Hospital as training cohort while data of 250 participants from Linyi People's Hospital were collected as validation cohort. Cox proportional hazards model was used to construct the nomogram and individually predicted 1-, 3-, and 5-year survival probabilities. Calibration ability, and discrimination ability were analyzed in both training and validation cohort. Results: Overall survival was negatively associated with histopathology, age, subtotal resection, multiple tumors, lower KPS and midline tumors. Internal validation and external validation showed good discrimination (The C-index for 1-, 3-, and 5-year survival were 0.791, 0.748, 0.733 in internal validation and 0.754, 0.735, 0.730 in external validation, respectively). The calibration curves showed good agreement between the predicted and actual 1-, 3-, and 5-year OS rates. Conclusion: This is the first nomogram study that integrates common clinicopathological factors to provide an individual probabilistic prognosis prediction for Chinese Han patients with astrocytoma (grades II-III). This model can serve as an easy-to-use tool to advise patients and establish optimized surveillance approaches after surgery. Supplementary Information: The online version contains supplementary material available at 10.1007/s13755-023-00223-0.

Epigenome-wide association study in Chinese monozygotic twins identifies DNA methylation loci associated with blood pressure.

BACKGROUND: Hypertension is a crucial risk factor for developing cardiovascular disease and reducing life expectancy. We aimed to detect DNA methylation (DNAm) variants potentially related to systolic blood pressure (SBP) and diastolic blood pressure (DBP) by conducting epigenome-wide association studies in 60 and 59 Chinese monozygotic twin pairs, respectively. METHODS: Genome-wide DNA methylation profiling in whole blood of twins was performed using Reduced Representation Bisulfite Sequencing, yielding 551,447 raw CpGs. Association between DNAm of single CpG and blood pressure was tested by applying generalized estimation equation. Differentially methylated regions (DMRs) were identified by comb-P approach. Inference about Causation through Examination of Familial Confounding was utilized to perform the causal inference. Ontology enrichment analysis was performed using Genomic Regions Enrichment of Annotations Tool. Candidate CpGs were quantified using Sequenom MassARRAY platform in a community population. Weighted gene co-expression network analysis (WGCNA) was conducted using gene expression data. RESULTS: The median age of twins was 52 years (95% range 40, 66). For SBP, 31 top CpGs (p < 1 × 10-4) and 8 DMRs were identified, with several DMRs within NFATC1, CADM2, IRX1, COL5A1, and LRAT. For DBP, 43 top CpGs (p < 1 × 10-4) and 12 DMRs were identified, with several DMRs within WNT3A, CNOT10, and DAB2IP. Important pathways, such as Notch signaling pathway, p53 pathway by glucose deprivation, and Wnt signaling pathway, were significantly enriched for SBP and DBP. Causal inference analysis suggested that DNAm at top CpGs within NDE1, MYH11, SRRM1P2, and SMPD4 influenced SBP, while SBP influenced DNAm at CpGs within TNK2. DNAm at top CpGs within WNT3A influenced DBP, while DBP influenced DNAm at CpGs within GNA14. Three CpGs mapped to WNT3A and one CpG mapped to COL5A1 were validated in a community population, with a hypermethylated and hypomethylated direction in hypertension cases, respectively. Gene expression analysis by WGCNA further identified some common genes and enrichment terms. CONCLUSION: We detect many DNAm variants that may be associated with blood pressure in whole blood, particularly the loci within WNT3A and COL5A1. Our findings provide new clues to the epigenetic modification underlying hypertension pathogenesis.

Identifying genetic variants regulating MGMT gene expression - A study in monozygotic Danish twins.

Identifying genetic factors affecting the regulation of the O-6-Methylguanine-DNA Methyltransferase (MGMT) gene and estimating the genetic contribution of the MGMT gene through within-pair correlation in monozygotic twin pairs is of particular importance in various types of cancer such as glioblastoma. We used gene expression data in whole blood from 448 monozygotic twins from the Middle Age Danish Twins (MADT) study to investigate genetic regulation of the MGMT gene by performing a genome-wide association study (GWAS) of the variation in MGMT expression. Additionally, we estimated within-pair dependence measures of the expression values looking for the genetic influence of significant identified genes. We identified 243 single nucleotide polymorphisms (SNPs) significantly (p < 5e-8) associated with expression of MGMT, all located on chromosome 10 near the MGMT gene. Of the 243 SNPs, 7 are novel cis-eQTLs. By further looking into the suggestively significant SNPs (increasing cutoff to p = 1e-6), we identified 11 suggestive trans-eQTLs located on chromosome 17. These variants were in or proximal to a total of seven genes, which may regulate MGMT expression. The within-pair correlation of the expression of MGMT, TRIM37, and SEPT4 provided the upper bound genetic influence of these genes. Overall, identifying cis- or trans-acting genetic variations regulating the MGMT gene can pave the way for a better understanding of the MGMT gene function and ultimately in understanding the patient's sensitivity to therapeutic alkylating agents.

A variability in response of osteoclasts to zoledronic acid is mediated by smoking-associated modification in the DNA methylome.

BACKGROUND: Clinical trials have shown zoledronic acid as a potent bisphosphonate in preventing bone loss, but with varying potency between patients. Human osteoclasts ex vivo reportedly displayed a variable sensitivity to zoledronic acid > 200-fold, determined by the half-maximal inhibitory concentration (IC50), with cigarette smoking as one of the reported contributors to this variation. To reveal the molecular basis of the smoking-mediated variation on treatment sensitivity, we performed a DNA methylome profiling on whole blood cells from 34 healthy female blood donors. Multiple regression models were fitted to associate DNA methylation with ex vivo determined IC50 values, smoking, and their interaction adjusting for age and cell compositions. RESULTS: We identified 59 CpGs displaying genome-wide significance (p < 1e-08) with a false discovery rate (FDR) < 0.05 for the smoking-dependent association with IC50. Among them, 3 CpGs have p < 1e-08 and FDR < 2e-03. By comparing with genome-wide association studies, 15 significant CpGs were locally enriched (within < 50,000 bp) by SNPs associated with bone and body size measures. Furthermore, through a replication analysis using data from a published multi-omics association study on bone mineral density (BMD), we could validate that 29 out of the 59 CpGs were in close vicinity of genomic sites significantly associated with BMD. Gene Ontology (GO) analysis on genes linked to the 59 CpGs displaying smoking-dependent association with IC50, detected 18 significant GO terms including cation:cation antiporter activity, extracellular matrix conferring tensile strength, ligand-gated ion channel activity, etc. CONCLUSIONS: Our results suggest that smoking mediates individual sensitivity to zoledronic acid treatment through epigenetic regulation. Our novel findings could have important clinical implications since DNA methylation analysis may enable personalized zoledronic acid treatment.

Development and validation of a 13-gene signature associated with immune function for the detection of Alzheimer's disease.

Current knowledge of Alzheimer's disease (AD) etiology and effective therapy remains limited. Thus, the identification of biomarkers is crucial to improve the detection and treatment of patients with AD. Using robust rank aggregation method to analyze the microarray data from Gene Expression Omnibus database, we identified 1138 differentially expressed genes in AD. We then explored 13 hub genes by weighted gene co-expression network analysis, least absolute shrinkage, and selection operator, and logistic regression in the training dataset. The detection model, which composed of CD163, CDC42SE1, CECR6, CSF1R, CYP27A1, EIF4E3, H2AFJ, IFIT2, IL10RA, KIAA1324, PSTPIP1, SLA, and TBC1D2 genes, along with APOE gene, showed that the area under the curve for detecting AD was 0.821 (95% confidence interval [CI] = 0.782-0.861) and the model was validated in ADNI dataset (area under the curve = 0.776; 95%CI = 0.686-0.865). Notably, the 13 genes in the model were highly enriched in immune function. These findings have implications for the detection and therapeutic target of AD.

Associations of WWC1 variants with Alzheimer's disease and vascular dementia among rural older adults in China: A population-based study.

We sought to examine the associations of common WWC1 variants with Alzheimer's disease (AD) and vascular dementia (VaD) among rural-dwelling older adults in China. This population-based study used data from the baseline assessments (March -September 2018) of MIND-China. AD and VaD were diagnosed following the international criteria. Of the 5455 participants (age≥60 years, 57.27% women), 182 were diagnosed with AD and 88 with VaD. Logistic regression analysis suggested that WWC1 rs17070145 C allele (vs. T) was associated with multivariable-adjusted odds ratio of 1.23 (95% confidence interval 0.96-1.58) for AD, and that CC genotype (vs. TT) was associated with multivariable-adjusted odds ratio of 2.19(1.10-4.39) for VaD, but the association with VaD became non-significant when further adjusting for stroke history. Furthermore, exonic SNPs rs3822660 and rs3822659 were in strong linkage disequilibrium (LD) with rs17070145 (D' = 0.88). These results suggest that the strong LD between rs17070145 and 2 exonic SNPs may explain the association of WWC1 rs17070145 C allele with AD and that stroke may partly explain the association of WWC1 rs17070145 CC genotype with VaD.

Mediation by DNA methylation on the association of BMI and serum uric acid in Chinese monozygotic twins.

Obesity is an established risk factor for hyperuricemia, but the mechanisms are only partially understood. We examined whether BMI-related DNA methylation (DNAm) variation would mediate the association of BMI with serum uric acid (SUA). We first conducted an epigenome-wide association analysis (EWAS) in 64 monozygotic twin pairs to detect BMI-related DNAm variation and then evaluated the mediated effect of DNAm using mediation analysis. Ontology enrichments analysis was performed for CpGs using GREAT tool. The genes where the candidate CpG mediators mapped were validated using gene expression data. BMI was positively associated with log10 transformed SUA level (ß = 0.01, P < 0.001). The association between BMI and DNAm of 138 CpGs reached P < 1 × 10-4 level. Twenty BMI-related differentially methylated regions within MAP2K2, POU4F2, AGAP2, MRGPRE, ADM5, and NKX1-1 were found. Of the 138 CpGs, 4 within VENTX (involved in cellular responses to stress pathway), SMOC2 (enable calcium ion binding), and FSCN2 (a member of fascin protein family) mediated the association between BMI and SUA, with a mediating effect of 0.002-µmol/L lower log10 transformed SUA levels and a proportion of 18.89 %-24.92 % negative mediating effect. BMI × DNAm interactions on SUA were observed for 2 CpGs within VENTX. The gene expression level of VENTX was also negatively associated with SUA level. BMI-related DNAm variation may partially mediate the association of BMI with SUA.

Circulating microRNAs related to lipid metabolism and solid tissue maintenance and morphology associate with mortality in elderly twins.

The lifespan of humans varies greatly between individuals. Here, we aimed to explore what biological roles miRNAs may have on old age mortality-variation. Circulating miRNAs were measured in plasma from 43 monozygotic twin pairs (73-95 years of age) and mortality analyses were applied using Cox regression survival analyses and linear regression analyses of lifespan. In general, nominally significant miRNAs were mainly upregulated with shorter lifespan, both in Cox analysis (72 % upregulated) and in linear regression analysis (81 % upregulated). A total of 29 miRNAs were associated to mortality at a nominal significance level (p < 0.05) in the survival analysis, but no miRNAs passed the FDR adjusted level of significance. Seven of the 29 miRNAs; hsa-miR-140-3p, hsa-miR-16-5p, hsa-miR-487b-3p, hsa-miR-19a-3p, hsa-let-7d-5p, hsa-miR-320a, hsa-miR-375, were nominally significant across two linear twin-paired analyses and the cox analysis. Pathway analyses of the 29 nominally significant miRNAs from the individual level analyses resulted in two nominally significant associated Reactome pathways (unadjusted p < 0.05); 'Negative regulation of FGFR signaling' and 'Neurotransmitter receptor binding and downstream transmission in the postsynaptic cell', and two significantly associated KEGG pathways; 'Linoleic acid metabolism' and 'Toxoplasmosis'. Additional pathway analyses and results of previous studies support that miRNAs linked to mortality at age 70 years or older play a role in lipid metabolism, tissues maintenance and morphology.

Smoking remains associated with education after controlling for social background and genetic factors in a study of 18 twin cohorts.

We tested the causality between education and smoking using the natural experiment of discordant twin pairs allowing to optimally control for background genetic and childhood social factors. Data from 18 cohorts including 10,527 monozygotic (MZ) and same-sex dizygotic (DZ) twin pairs discordant for education and smoking were analyzed by linear fixed effects regression models. Within twin pairs, education levels were lower among the currently smoking than among the never smoking co-twins and this education difference was larger within DZ than MZ pairs. Similarly, education levels were higher among former smoking than among currently smoking co-twins, and this difference was larger within DZ pairs. Our results support the hypothesis of a causal effect of education on both current smoking status and smoking cessation. However, the even greater intra-pair differences within DZ pairs, who share only 50% of their segregating genes, provide evidence that shared genetic factors also contribute to these associations.

Early life affects late-life health through determining DNA methylation across the lifespan: A twin study.

BACKGROUND: Previous findings for the genetic and environmental contributions to DNA methylation variation were for limited age ranges only. We investigated the lifespan contributions and their implications for human health for the first time. METHODS: 1,720 monozygotic twin (MZ) pairs and 1,107 dizygotic twin (DZ) pairs aged 0-92 years were included. Familial correlations (i.e., correlations between twins) for 353,681 methylation sites were estimated and modelled as a function of twin pair cohabitation history. FINDINGS: The methylome average familial correlation was around zero at birth (MZ pair: -0.01; DZ pair: -0.04), increased with the time of twins living together during childhood at rates of 0.16 (95%CI: 0.12-0.20) for MZ pairs and 0.13 (95%CI: 0.07-0.20) for DZ pairs per decade, and decreased with the time of living apart during adulthood at rates of 0.026 (95%CI: 0.019-0.033) for MZ pairs and 0.027 (95%CI: 0.011-0.043) for DZ pairs per decade. Neither the increasing nor decreasing rate differed by zygosity (both P>0.1), consistent with cohabitation environment shared by twins, rather than genetic factors, influencing the methylation familial correlation changes. Familial correlations for 6.6% (23,386/353,681) sites changed with twin pair cohabitation history. These sites were enriched for high heritability, proximal promoters, and epigenetic/genetic associations with various early-life factors and late-life health conditions. INTERPRETATION: Early life strongly influences DNA methylation variation across the lifespan, and the effects are stronger for heritable sites and sites biologically relevant to the regulation of gene expression. Early life could affect late-life health through influencing DNA methylation. FUNDING: Victorian Cancer Agency, Cancer Australia, Cure Cancer Foundation.

Distribution of 54 polygenic risk scores for common diseases in long lived individuals and their offspring.

A surprising and well-replicated result in genetic studies of human longevity is that centenarians appear to carry disease-associated variants in numbers similar to the general population. With the proliferation of large genome-wide association studies (GWAS) in recent years, investigators have turned to polygenic scores to leverage GWAS results into a measure of genetic risk that can better predict the risk of disease than individual significant variants alone. We selected 54 polygenic risk scores (PRSs) developed for a variety of outcomes, and we calculated their values in individuals from the New England Centenarian Study (NECS, N = 4886) and the Long Life Family Study (LLFS, N = 4577). We compared the distribution of these PRSs among exceptionally long-lived individuals (ELLI), their offspring, and controls, and we also examined their predictive values, using t-tests and regression models adjusting for sex and principal components reflecting the ancestral background of the individuals (PCs). In our analyses, we controlled for multiple testing using a Bonferroni-adjusted threshold for 54 traits. We found that only 4 of the 54 PRSs differed between ELLIs and controls in both cohorts. ELLIs had significantly lower mean PRSs for Alzheimer's disease (AD) and coronary artery disease (CAD) than controls, suggesting a genetic predisposition to extreme longevity may be mediated by reduced susceptibility to these traits. ELLIs also had significantly higher mean PRSs for improved cognitive function and parental extreme longevity. In addition, the PRS for AD was associated with a higher risk of dementia among controls but not ELLIs (p = 0.003, 0.3 in NECS, p = 0.03, 0.9 in LLFS, respectively). ELLIs have a similar burden of genetic disease risk as the general population for most traits but have a significantly lower genetic risk of AD and CAD. The lack of association between AD PRS and dementia among ELLIs suggests that the genetic risk for AD that they do have is somehow counteracted by protective genetic or environmental factors.

Analysis of genetic and environmental correlation between leisure activities and cognitive function in aging Chinese twins.

OBJECTIVE: Leisure activity has been shown to be beneficial to mental health and cognitive aging. The biological basis of the correlation is, however, poorly understood. This study aimed at exploring the genetic and environmental impacts on correlation between leisure activities and cognitive function in the Chinese middle- and old-aged twins. METHODS: Cognition measured using a screening test (Montreal Cognitive Assessment, MoCA) and leisure activities including intellectual and social activity were investigated on 379 complete twin pairs of middle- and old-aged twins. Univariate and bivariate twin models were fitted to estimate the genetic and environmental components in their variance and covariance. RESULTS: Moderate heritability was estimated for leisure activities and cognition (0.44-0.53) but insignificant for social activity. Common environmental factors accounted for about 0.36 of the total variance to social activity with no significant contribution to leisure activity, intellectual activity and cognition. Unique environmental factors displayed moderate contributions (0.47-0.64) to leisure activities and cognition. Bivariate analysis showed highly and positively genetic correlations between leisure activities and cognition (rG=0.80-0.96). Besides, intellectual activity and cognition presented low but significant unique environmental correlation (rE=0.12). CONCLUSIONS: Genetic factor had the moderate contribution to leisure activities and cognition. Cognitive function was highly genetically related to leisure activities. Intellectual activity and cognitive function may share some unique environmental basis.