Familial Segregation of Venous Thromboembolism in Sweden: A Nationwide Family Study of Heritability and Complex Segregation Analysis

Background This is the first nationwide segregation analysis that aimed to determine whether familial venous thromboembolism (VTE) is attributable to inheritance and/or shared environment, and the possible mode of inheritance. Methods and Results The Swedish Multi‐Generation Register was linked to the Swedish patient register for the period 1964 to 2015. Three generational families of Swedish‐born individuals were identified. Heritability was examined using Falconer regression. Complex segregation analysis was conducted using the Statistical Analysis for Genetic Epidemiology software (version 6.4, 64‐bit Linux). Among the 4 301 174 relatives from 450 558 pedigrees, 177 865 (52% women) individuals were affected with VTE. VTE occurred in 2 or more affected relatives in 61 217 (13.6%) of the pedigrees. Heritability showed age and sex dependence with higher heritability for men and young individuals. In 18 933 pedigrees, VTE occurred only in the first generation and was not inherited. Segregation analysis was performed in the remaining 42 284 pedigrees with inherited VTE and included 939 192 individuals. Prevalence constraints were imposed in the models to allow for the selection of the pedigrees analyzed. The sporadic nongenetic model could be discarded. The major‐type‐only model, with a correlation structure compatible with some polygenic effects, was the preferred model. Among the Mendelian models, the mixed codominant (plus polygenic) model was preferred. Conclusions This nationwide segregation analysis of VTE supports a genetic cause of the familial aggregation of VTE. Heritability was higher for men and younger individuals, suggesting a Carter effect, in agreement with a multifactorial threshold inheritance.

Association of Leukocyte Telomere Length With Perceived Physical Fatigability

Leukocyte telomere length (LTL) is a potential marker of biological aging, but its relationship to fatigability, a prognostic indicator of phenotypic aging (e.g., functional decline) is unknown. We hypothesized shorter LTL would predict greater perceived physical fatigability. Two generations of participants (N=1,997; 309 probands, 1,688 offspring) were from the Long Life Family Study (age=73.7±10.4, range 60-108, 54.4% women). LTL was assayed at baseline and 8.0±1.1 years later perceived physical fatigability was measured using the validated, self-administered 10-item Pittsburgh Fatigability Scale (PFS, 0-50, higher scores=greater fatigability). Prevalence of greater physical fatigability (PFS scores≥15) was 41.9%. Using multivariate linear regression, one kilobase pair shorter LTL predicted higher PFS Physical scores (β=0.9, p=0.025), adjusted for family relatedness, generation (indicator for age), field center, follow-up time, sex, and follow-up body mass index, physical activity, health conditions. LTL, a promising marker of future fatigability, may allow for early identification of those at-risk for deleterious aging.

Discovering Modality of Cognitive Function Using Clustering Analysis

In this study with Long Life Family Study (LLFS) participants, we aimed to identify patterns of performance on cognitive function assessments as specific cognitive signatures. We hypothesize that such signatures can be correlated with biomarkers and clinical outcomes. More than 4,700 LLFS participants were administered, at enrollment, a series of neuropsychological tests that measure various cognitive domains. We performed a cluster analysis to group LLFS subjects into clusters characterized by combinations of six neuropsychological test scores. The analysis resulted in 10 clusters of varying size with different cognitive signatures that (1) significantly correlated with physical and pulmonary function, and 31 blood biomarkers and (2) predicted mortality and incident medical events such as dementia, cardiovascular diseases, etc. We conclude that cluster analysis of multiple neuropsychological tests discovers cognitive signatures that are more specific than individual cognitive domains and that these can be correlated with blood biomarkers, incident medical outcomes and mortality.

Genes Involved in Physiological Dysregulation and Decline in Resilience: Role in Alzheimer’s Disease

Our recent GWAS of a composite measure of physiological dysregulation (PD) in the Long Life Family Study (LLFS) found that the top genes associated with age-related changes in PD are involved in biological pathways relevant to maintaining neural networks and brain resilience. In our prior work, PD itself was linked to resilience-related traits. Alzheimer’s disease (AD) is a heterogeneous trait and it may involve an accelerated decline in resilience with age as a contributing factor. We proposed that genes associated with aging-changes in PD and brain resilience may contribute to AD risk. We investigated interactions between SNPs in such candidate genes with AD in LLFS and Health and Retirement Study (HRS). Our analysis revealed significant interactions between SNPs in UNC5C and other genes with AD, in both LLFS and HRS. These findings support roles of genetic interactions with UNC5C gene (implemented in axon growth and neuronal apoptosis) in AD.

Linkage Guided Sequence Analysis Revealed a Novel Gene PKD1L2 for Adiponectin: The Long Life Family Study (LLFS)

Adiponectin is involved in regulating insulin resistance (IR) and is a potential regulator of healthy aging and lifespan. To identify novel variants associated with adiponectin, we further assessed our previously identified linkage peak on 16q23.2 (LODs=3.8). We used sequence data of 632 participants (age, 24-110 years) from 47 families of European ancestry in the Long Life Family Study, a study with familial clustering of exceptional longevity in the US and Denmark. Adiponectin levels were log-transformed, and adjusted for age, sex, sites, and PCs for ancestry. We found a variant in the PKD1L2 (rs527459046, p=2e-8, MAF=3%, r2=1.5%, accounting for linkage=28%). The PKD1L2, 1.4 Mb upstream of the CDH13 (adiponectin receptor gene) is expressed in heart, liver, and adipocytes, known to function as an ion-channel regulator or a GPCR regulator for aging-related lipolysis, IR, and adiponectin/leptin secretion. Haplotyping, epistatic and bioinformatic analyses will be engaged to capture additional/functional variants and regulatory networks.

Using Threshold Regression as an Approach to Incorporate Informative Missingness in Long Life Family Study Data

Genetics of aging is important since aging is a major risk factor in most diseases. Variables describing physiological state and cognitive functioning that influence morbidity and mortality risks can serve as biomarkers of aging. They change with increasing age and the ways in which these variables change can also influence these risks. Missing data due to dropout or death create problems in longitudinal studies producing biased results especially if the gap between exams is relatively long, as is the case in the Long Life Family Study (LLFS). We applied the threshold regression model to LLFS data to investigate the vitality and its rate, which are conceptualized as latent variables characterizing health and longevity, and to cope with such a problem. We performed genome-wide association study by sex and age groups to discover genetic signals on these phenotypes. We found 11 variants from the DACT2 gene, p-values < 1E-6 and variants rs12151399 (p-value = 8.43E-8, intron variant, gene AGAP1, in females), rs27958 (p-value = 8.39E-8, intron variant, gene ARHGAP26, in males) showing associations with the vitality. Olfactory receptors showed significant enrichment among the group of males over 80 years for the rate of aging phenotype. Results showed that vitality and its rate differ among sex and age groups. This work is an important step toward understanding the processes of aging linking the vitality with individual genetics using data from deceased and living individuals.

Metabolomic Profile Differences Between Demented and Non-Demented APOE4 Carriers in the Long Life Family Study

The apolipoprotein ε4 (APOE4) is the most prevalent genetic risk factor for late-onset Alzheimer’s Disease (AD). Here we assessed the metabolomic profile differences between APOE4 carriers who develop AD vs. who do not in a sample of 142 participants, aged 65-99 years in the Long Life Family Study (LLFS). Of 7,321 metabolites, we applied a generalized estimating equation model and identified 137 metabolites significantly associated with AD. Subsequent multivariate analyses were performed for prediction and clustering recognition. Among annotated metabolites, 8 metabolites in the eicosanoids and docosanoids group, 3 metabolites in the fatty acids group, and arabitol were associated with elevated risks of AD (OR: 1.6-2.3). On the other hand, a different set of metabolites were associated with reduced risks of AD (OR: 0.34-0.64). These metabolomic profile differences can be used to help with early diagnosis in the population of older APOE4 carriers in the pre-clinical stage.