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

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 582-583
Author(s):  
Joseph Lee ◽  
Jason Anema ◽  
Lihua Wang ◽  
Warwick Daw ◽  
Kaare Christensen ◽  
...  
Keyword(s):  
Regulatory Networks ◽  
Healthy Aging ◽  
Family Study ◽  
Sequence Data ◽  
Receptor Gene ◽  
Linkage Peak ◽  
European Ancestry ◽  
Functional Variants ◽  
Novel Variants ◽  
Long Life

Abstract 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.

A comparison of genetic imputation methods using Long Life Family Study genotypes and sequence data with the 1000 Genome reference panel

2020 ◽  
Vol 16 (1) ◽  
pp. 59
Author(s):  
Christine A. Williams ◽  
Thomas Perls ◽  
Alan B. Wells ◽  
Kathryn L. Lunetta ◽  
Joanne M. Murabito ◽  
...  
Keyword(s):  
Family Study ◽  
Sequence Data ◽  
Reference Panel ◽  
Imputation Methods ◽  
Long Life

scholarly journals Candidate gene resequencing to identify rare, pedigree-specific variants influencing healthy aging phenotypes in the long life family study

2016 ◽  
Vol 16 (1) ◽  
Author(s):  
Todd E. Druley ◽  
Lihua Wang ◽  
Shiow J. Lin ◽  
Joseph H. Lee ◽  
Qunyuan Zhang ◽  
...  
Keyword(s):  
Candidate Gene ◽  
Healthy Aging ◽  
Family Study ◽  
Long Life

Identification of a Novel Locus for Gait Speed Decline with Aging: The Long Life Family Study

2021 ◽  
Author(s):  
Adam J Santanasto ◽  
Mary K Wojczynski ◽  
Ryan K Cvejkus ◽  
Shiow Lin ◽  
Lihua Wang ◽  
...  
Keyword(s):  
Gait Speed ◽  
Family Study ◽  
Linkage Peak ◽  
Chromosome 16 ◽  
Association Analyses ◽  
Genome Wide ◽  
Maximum Likelihood Methods ◽  
Significant Locus ◽  
Long Life ◽  
Genetic Contributions

Abstract Background Gait speed is a powerful indicator of health with aging. Potential genetic contributions to gait speed and its decline with aging are not well defined. We determined the heritability of and potential genetic regions underlying change in gait speed using longitudinal data from 2379 individuals belonging to 509 families in the Long Life Family Study (mean age 64±12, range 30–110 years; 45% men). Methods Gait-speed was measured over 4 meters at baseline and follow up (7±1 years). Quantitative trait linkage analyses were completed using pedigree-based maximum-likelihood methods with logarithm of the odds (LOD) scores >3.0 indicating genome-wide significance. We also performed linkage analysis in the top 10% of families contributing to LOD scores to allow for heterogeneity among families (HLOD). Data were adjusted for age, sex, height, and field center. Results At baseline, 26.9% of individuals had “slow” gait-speed <1.0 m/s (mean: 1.1±0.2 m/s) and gait speed declined at a rate of -0.02±0.03 m/s per year (p<0.0001). Baseline and change in gait-speed were significantly heritable (h  2 = 0.24-0.32, p<0.05). We did not find significant evidence for linkage for baseline gait speed; however, we identified a significant locus for change in gait speed on chromosome 16p (LOD=4.2). A subset of 21 families contributed to this linkage peak (HLOD = 6.83). Association analyses on chromosome 16 showed that the strongest variant resides within the ADCY9 gene. Conclusion Further analysis of the chromosome 16 region, and ADCY9 gene, may yield new insight on the biology of mobility decline with aging.

scholarly journals Association Between APOE Alleles and Change of Neuropsychological Tests in the Long Life Family Study

2021 ◽  
Vol 79 (1) ◽  
pp. 117-125
Author(s):  
Mengtian Du ◽  
Stacy L. Andersen ◽  
Nicole Schupf ◽  
Mary F. Feitosa ◽  
Megan S. Barker ◽  
...  
Keyword(s):  
Older Adults ◽  
Cognitive Function ◽  
Test Scores ◽  
Healthy Aging ◽  
Family Study ◽  
Apoe Genotype ◽  
Cognitive Test ◽  
Cross Sectional ◽  
Long Life ◽  
E4 Allele

Background: The Long Life Family Study (LLFS) is a family based, prospective study of healthy aging and familial longevity. The study includes two assessments of cognitive function that were administered approximately 8 years apart. Objective: To test whether APOE genotype is associated with change of cognitive function in older adults. Methods: We used Bayesian hierarchical models to test the association between APOE alleles and change of cognitive function. Six longitudinally collected neuropsychological test scores were modelled as a function of age at enrollment, follow-up time, gender, education, field center, birth cohort indicator (≤1935, or >1935), and the number of copies of ɛ2 or ɛ4 alleles. Results: Out of 4,587 eligible participants, 2,064 were male (45.0%), and age at enrollment ranged from 25 to 110 years, with mean of 70.85 years (SD: 15.75). We detected a significant cross-sectional effect of the APOE ɛ4 allele on Logical Memory. Participants carrying at least one copy of the ɛ4 allele had lower scores in both immediate (–0.31 points, 95% CI: –0.57, –0.05) and delayed (–0.37 points, 95% CI: –0.64, –0.10) recall comparing to non-ɛ4 allele carriers. We did not detect any significant longitudinal effect of the ɛ4 allele. There was no cross-sectional or longitudinal effect of the ɛ2 allele. Conclusion: The APOE ɛ4 allele was identified as a risk factor for poorer episodic memory in older adults, while the APOE ɛ2 allele was not significantly associated with any of the cognitive test scores.

scholarly journals Long Life Family Study Shows Reduced Coronary Artery Disease Despite High Polygenic Hazard Scores

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 212-212
Author(s):  
Mary Feitosa ◽  
Allison Kuipers ◽  
Mary Wojczynski ◽  
Lihua Wang ◽  
Thomas Perls ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Proportional Hazards ◽  
Family Study ◽  
Age At Onset ◽  
Cox Proportional Hazards ◽  
European Ancestry ◽  
Long Life ◽  
Artery Disease ◽  
Cad Risk

Abstract Polygenic hazard scores (PHS) for coronary artery disease (CAD) quantify individuals with age-specific genetic risk for CAD. We evaluated how well the PHS predict age at onset of CAD in the Long Life Family Study (LLFS; families selected for exceptional longevity), compared to the Family Heart Study (FamHS; random families and high CAD-risk families). LLFS contains 4572 European ancestry (EA) individuals from 581 families (age: 74.0 ± 14.3, range: 22-110 years). FamHS Random has 1806 EA individuals from 454 families (age: 56.2 ± 13.5, range: 22-91 years), while FamHS High CAD-risk has 2301 EA individuals from 553 families (age: 53.2 ± 12.8, range: 21-93 years). We generated the PHS from 176 published SNPs from GWAS for CAD (p< 5.0 x 10-8, r2< 0.2). In each of the extremes of the CAD PHS distributions (75%), Kaplan-Meier method showed that the LLFS presented significant delayed age at onset of CAD compared to FamHS (random and High CAD-risk: P<0.0001). A Cox proportional hazards regression model accounting for CAD age at onset, using family bootstrap (N= 1000) to correct for family relatedness, replicated these results. For example, in the top-25% CAD-PHS when comparing to FamHS high-risk, the LLFS CAD hazards ratio was 0.127 (95% CI: 0.099, 0.164). Our findings suggest that, while PHS captured some of the risk of CAD in LLFS, part of the predisposition remains to be determined. Other relevant factors, including additional genetic discoveries and lifestyle-environment influences are needed to fully determine CAD risk in extreme samples.

scholarly journals Genome-Wide Linkage Analysis Identifies a Novel Locus for Grip Strength: The Long Life Family Study

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 142-142
Author(s):  
Adam Santanasto ◽  
Mary Wojczynski ◽  
Ryan Cvejkus ◽  
Bharat Thygarajan ◽  
Kaare Christensen ◽  
...  
Keyword(s):  
Linkage Analysis ◽  
Grip Strength ◽  
Family Study ◽  
Linkage Peak ◽  
Treatment And Prevention ◽  
Quantitative Trait Linkage Analysis ◽  
Genome Wide ◽  
European Working ◽  
Maximum Likelihood Methods ◽  
Long Life

Abstract Grip strength declines with aging, is an indicator of overall health, and predicts mortality among older adults. Herein, we quantified the genetic contributions to grip strength among 4534 individuals, belonging to 574 families in the Long Life Family Study (age 70.3 ± 15.7, range 24–110 years; 56% women). Grip strength was measured using a handheld dynamometer, and the maximum value of two trials in the stronger hand was used. Quantitative trait linkage analysis was completed using pedigree-based maximum-likelihood methods with logarithm of the odds (LOD) scores >3.0 indicating genome-wide significance. Linkage analysis in the top 10% of families contributing to LOD scores was also performed to allow for heterogeneity among families (HLOD). All analyses were adjusted for age, sex, height and field center. Grip strength was lower per one year of older age (β: -0.34 ± 0.01kg, p <0.01), and overall: 24.3% of men and 19.3% of women had “low” grip strength according to European Working Group on Sarcopenia definitions. Grip strength was highly heritable (h2 = 0.37, p<0.05). We identified a potentially novel locus for grip strength on chromosome 18p (LOD 3.18) with 26 families contributing to this linkage peak (HLOD = 10.94). Deep sequencing of the chromosome 18 region may yield fundamental insight on the biology of muscle weakness with aging, and may help identify novel therapeutic targets for treatment and prevention of this common condition.

Sign in / Sign up

Export Citation Format

Share Document