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  • 1
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    Online Resource
    Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions
    Oxford University Press (OUP) ; 2019
    In:  American Journal of Epidemiology Vol. 188, No. 6 ( 2019-06-01), p. 1033-1054
    Details
    In: American Journal of Epidemiology, Oxford University Press (OUP), Vol. 188, No. 6 ( 2019-06-01), p. 1033-1054
    Type of Medium: Online Resource
    ISSN: 0002-9262 , 1476-6256
    URL: Article
    DOI: 10.1093/aje/kwz005
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2019
    detail.hit.zdb_id: 2030043-8
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  • 2
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    A multi-ancestry genome-wide study incorporating gene–smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure
    Oxford University Press (OUP) ; 2019
    In:  Human Molecular Genetics Vol. 28, No. 15 ( 2019-08-01), p. 2615-2633
    Details
    In: Human Molecular Genetics, Oxford University Press (OUP), Vol. 28, No. 15 ( 2019-08-01), p. 2615-2633
    Abstract: Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene–smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene–smoking interaction analysis and 38 were newly identified (P  〈  5 × 10−8, false discovery rate  〈  0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings.
    Type of Medium: Online Resource
    ISSN: 0964-6906 , 1460-2083
    URL: Article
    DOI: 10.1093/hmg/ddz070
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2019
    detail.hit.zdb_id: 1474816-2
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  • 3
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    Dairy Consumption and Body Mass Index Among Adults: Mendelian Randomization Analysis of 184802 Individuals from 25 Studies
    Oxford University Press (OUP) ; 2018
    In:  Clinical Chemistry Vol. 64, No. 1 ( 2018-01-01), p. 183-191
    Details
    In: Clinical Chemistry, Oxford University Press (OUP), Vol. 64, No. 1 ( 2018-01-01), p. 183-191
    Abstract: Associations between dairy intake and body mass index (BMI) have been inconsistently observed in epidemiological studies, and the causal relationship remains ill defined. METHODS We performed Mendelian randomization (MR) analysis using an established dairy intake-associated genetic polymorphism located upstream of the lactase gene (LCT-13910 C/T, rs4988235) as an instrumental variable (IV). Linear regression models were fitted to analyze associations between (a) dairy intake and BMI, (b) rs4988235 and dairy intake, and (c) rs4988235 and BMI in each study. The causal effect of dairy intake on BMI was quantified by IV estimators among 184802 participants from 25 studies. RESULTS Higher dairy intake was associated with higher BMI (β = 0.03 kg/m2 per serving/day; 95% CI, 0.00–0.06; P = 0.04), whereas the LCT genotype with 1 or 2 T allele was significantly associated with 0.20 (95% CI, 0.14–0.25) serving/day higher dairy intake (P = 3.15 × 10−12) and 0.12 (95% CI, 0.06–0.17) kg/m2 higher BMI (P = 2.11 × 10−5). MR analysis showed that the genetically determined higher dairy intake was significantly associated with higher BMI (β = 0.60 kg/m2 per serving/day; 95% CI, 0.27–0.92; P = 3.0 × 10−4). CONCLUSIONS The present study provides strong evidence to support a causal effect of higher dairy intake on increased BMI among adults.
    Type of Medium: Online Resource
    ISSN: 0009-9147 , 1530-8561
    URL: Article
    DOI: 10.1373/clinchem.2017.280701
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2018
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  • 4
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    Identification of a Novel Locus for Gait Speed Decline With Aging: The Long Life Family Study
    Oxford University Press (OUP) ; 2021
    In:  The Journals of Gerontology: Series A Vol. 76, No. 10 ( 2021-09-13), p. e307-e313
    Details
    In: The Journals of Gerontology: Series A, Oxford University Press (OUP), Vol. 76, No. 10 ( 2021-09-13), p. e307-e313
    Abstract: 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 m 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 greater than 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 less than 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 & lt; .0001). Baseline and change in gait speed were significantly heritable (h2 = 0.24–0.32, p & lt; .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.
    Type of Medium: Online Resource
    ISSN: 1079-5006 , 1758-535X
    URL: Article
    DOI: 10.1093/gerona/glab177
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 2043927-1
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  • 5
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    Dairy Intake and Body Composition and Cardiometabolic Traits among Adults: Mendelian Randomization Analysis of 182041 Individuals from 18 Studies
    Oxford University Press (OUP) ; 2019
    In:  Clinical Chemistry Vol. 65, No. 6 ( 2019-06-01), p. 751-760
    Details
    In: Clinical Chemistry, Oxford University Press (OUP), Vol. 65, No. 6 ( 2019-06-01), p. 751-760
    Abstract: Associations between dairy intake and body composition and cardiometabolic traits have been inconsistently observed in epidemiological studies, and the causal relationship remains ill-defined. METHODS We performed Mendelian randomization analysis using an established genetic variant located upstream of the lactase gene (LCT-13910 C/T, rs4988235) associated with dairy intake as an instrumental variable (IV). The causal effects of dairy intake on body composition and cardiometabolic traits (lipids, glycemic traits, and inflammatory factors) were quantified by IV estimators among 182041 participants from 18 studies. RESULTS Each 1 serving/day higher dairy intake was associated with higher lean mass [β (SE) = 0.117 kg (0.035); P = 0.001], higher hemoglobin A1c [0.009% (0.002); P & lt; 0.001], lower LDL [−0.014 mmol/L (0.006); P = 0.013] , total cholesterol (TC) [−0.012 mmol/L (0.005); P = 0.023], and non-HDL [−0.012 mmol/L (0.005); P = 0.028] . The LCT-13910 C/T CT + TT genotype was associated with 0.214 more dairy servings/day (SE = 0.047; P & lt; 0.001), 0.284 cm higher waist circumference (SE = 0.118; P = 0.017), 0.112 kg higher lean mass (SE = 0.027; P = 3.8 × 10−5), 0.032 mmol/L lower LDL (SE = 0.009; P = 0.001), and 0.032 mmol/L lower TC (SE = 0.010; P = 0.001). Genetically higher dairy intake was associated with increased lean mass [0.523 kg per serving/day (0.170); P = 0.002] after correction for multiple testing (0.05/18). However, we find that genetically higher dairy intake was not associated with lipids and glycemic traits. CONCLUSIONS The present study provides evidence to support a potential causal effect of higher dairy intake on increased lean mass among adults. Our findings suggest that the observational associations of dairy intake with lipids and glycemic traits may be the result of confounding.
    Type of Medium: Online Resource
    ISSN: 0009-9147 , 1530-8561
    URL: Article
    DOI: 10.1373/clinchem.2018.300335
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2019
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  • 6
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    Perceived Physical Fatigability Predicts All-Cause Mortality in Older Adults
    Oxford University Press (OUP) ; 2022
    In:  The Journals of Gerontology: Series A Vol. 77, No. 4 ( 2022-04-01), p. 837-841
    Details
    In: The Journals of Gerontology: Series A, Oxford University Press (OUP), Vol. 77, No. 4 ( 2022-04-01), p. 837-841
    Abstract: Perceived physical fatigability is highly prevalent in older adults and associated with mobility decline and other health consequences. We examined the prognostic value of perceived physical fatigability as an independent predictor of risk of death among older adults. Methods Participants (N = 2 906), mean age 73.5 [SD, 10.4] years, 54.2% women, 99.7% white enrolled in the Long Life Family Study, were assessed at Visit 2 (2014–2017) with 2.7 [SD, 1.0] years follow-up. The Pittsburgh Fatigability Scale (PFS), a 10-item, self-administered validated questionnaire (score range 0–50, higher = greater fatigability) measured perceived physical fatigability at Visit 2. Deaths post-Visit 2 through December 31, 2019 were identified by family members notifying field centers, reporting during another family member’s annual phone follow-up, an obituary, or Civil Registration System (Denmark). We censored all other participants at their last contact. Cox proportional hazard models predicted mortality by fatigability severity, adjusted for family relatedness and other covariates. Results Age-adjusted PFS Physical scores were higher for those who died (19.1 [SE, 0.8]) compared with alive (12.2, [SE, 0.4] ) overall, as well as across age strata (p & lt; .001), except for those 60–69 years (p = .79). Participants with the most severe fatigability (PFS Physical scores ≥ 25) were over twice as likely to die (hazard ratio, 2.33 [95% CI, 1.65–3.28]) compared with those who had less severe fatigability (PFS Physical scores & lt; 25) after adjustment. Conclusions Our work underscores the utility of the PFS as a novel patient-reported prognostic indicator of phenotypic aging that captures both overt and underlying disease burden that predicts death.
    Type of Medium: Online Resource
    ISSN: 1079-5006 , 1758-535X
    URL: Article
    DOI: 10.1093/gerona/glab374
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 2043927-1
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  • 7
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    Prevalence, Incidence, and Risk Factors for Overall, Physical, and Cognitive Independence Among Those From Exceptionally Long-Lived Families: The Long Life Family Study
    Oxford University Press (OUP) ; 2020
    In:  The Journals of Gerontology: Series A Vol. 75, No. 5 ( 2020-04-17), p. 899-905
    Details
    In: The Journals of Gerontology: Series A, Oxford University Press (OUP), Vol. 75, No. 5 ( 2020-04-17), p. 899-905
    Abstract: The Long Life Family Study (LLFS) enrolled families exhibiting exceptional longevity. The goal of this article was to determine the prevalence and predictors of remaining independent after 7 years in the oldest generation. Methods We examined 7-year change in physical (free of activities of daily living difficulty), cognitive (Mini-Mental State Examination score ≥ 24), and overall independence (physically/cognitively independent) in adults aged 90.3 ± 6.3 from LLFS’s oldest generation. Potential predictors (n = 28) of remaining independent included demographics, diseases, biomarkers, anthropometrics, and physical and cognitive performance tasks and were determined using generalized estimating equations (α: p & lt; .05). This was a discovery/exploratory analysis, so no multiple testing correction was employed and the results require independent replication. Results At baseline (n = 1442), 67.3%, 83.8%, and 79.7% were overall, physically, and cognitively independent, respectively. After 7 years, 66% died, 7.5% were lost to follow-up, and the prevalence of overall independence decreased to 59.1% in survivors (−8.2%, 95% confidence interval: −14.1%, 2.2%). Of those with baseline independence, 156/226 (69.0%) remained independent. Predictors of remaining physically independent included younger age, better Short Physical Performance Battery score and lung function, smaller waist circumference, and lower soluble receptor for advanced glycation end-product levels (p & lt; .05). Predictors of remaining cognitively independent included no cancer history, better Digit Symbol Substitution Test performance, and higher body weight (p & lt; .05). Conclusions The prevalence of independence decreased by only 8.2% after 7 years, demonstrating the close correspondence between disability and mortality. Further, despite a mean baseline age of 90 years, a large proportion of survivors remained independent, suggesting this exceptional subgroup may harbor protective mechanisms.
    Type of Medium: Online Resource
    ISSN: 1079-5006 , 1758-535X
    URL: Article
    DOI: 10.1093/gerona/glz124
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
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  • 8
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    Relationship Between Serum IGF-1 and BMI Differs by Age
    Oxford University Press (OUP) ; 2021
    In:  The Journals of Gerontology: Series A Vol. 76, No. 7 ( 2021-06-14), p. 1303-1308
    Details
    In: The Journals of Gerontology: Series A, Oxford University Press (OUP), Vol. 76, No. 7 ( 2021-06-14), p. 1303-1308
    Abstract: Serum levels of insulin-like growth factor 1 (IGF-1) and body mass index (BMI) are both associated with susceptibility to age-related diseases. Reports on the correlation between them have been conflicting, with both positive to negative correlations reported. However, the age ranges of the participants varied widely among these studies. Methods Using data on 4241 participants (aged 24–110) from the Long Life Family Study, we investigated the relationship between IGF-1 and BMI by age groups using regression analysis. Results When stratified by age quartile, the relationship between IGF-1 and BMI varied: in the first quartile (Q1, 20–58 years) the relationship was negative (β = −0.2, p = .002); in Q2 (58–66 years) and Q3 (67–86 years) the relationship was negative (β = −0.07, β = −0.01, respectively) but nonsignificant; and in Q4 (87–110 years) the relationship was positive (β = 0.31, p = .0002). This pattern did not differ by sex. We observed a similar age-related pattern between IGF-1 and BMI among participants in the third National Health and Nutritional Examination Survey. Conclusions Our results that the relationship between IGF-1 and BMI differs by age may explain some of the inconsistency in reports about their relationship and encourage additional studies to understand the mechanisms underlying it.
    Type of Medium: Online Resource
    ISSN: 1079-5006 , 1758-535X
    URL: Article
    DOI: 10.1093/gerona/glaa282
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 2043927-1
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  • 9
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    Genetic Pleiotropy Between Pulmonary Function and Age-Related Traits: The Long Life Family Study
    Oxford University Press (OUP) ; 2022
    In:  The Journals of Gerontology: Series A ( 2022-02-18)
    Details
    In: The Journals of Gerontology: Series A, Oxford University Press (OUP), ( 2022-02-18)
    Abstract: Pulmonary function (PF) progressively declines with aging. Forced expiratory volume in the first second (FEV1) and forced vital capacity (FVC) are predictors of morbidity of pulmonary and cardiovascular diseases and all-cause mortality. In addition, reduced PF is associated with elevated chronic low-grade systemic inflammation, glucose metabolism, body fatness, and low muscle strength. It may suggest pleiotropic genetic effects between PF with these age-related factors. Methods We evaluated whether FEV1 and FVC share common pleiotropic genetic effects with interleukin-6, high-sensitivity C-reactive protein, body mass index, muscle (grip) strength, plasma glucose, and glycosylated hemoglobin in 3 888 individuals (age range: 26–106). We employed sex-combined and sex-specific correlated meta-analyses to test whether combining genome-wide association p values from 2 or more traits enhances the ability to detect variants sharing effects on these correlated traits. Results We identified 32 loci for PF, including 29 novel pleiotropic loci associated with PF and (i) body fatness (CYP2U1/SGMS2), (ii) glucose metabolism (CBWD1/DOCK8 and MMUT/CENPQ), (iii) inflammatory markers (GLRA3/HPGD, TRIM9, CALN1, CTNNB1/ZNF621, GATA5/SLCO4A1/NTSR1, and NPVF/C7orf31/CYCS), and (iv) muscle strength (MAL2, AC008825.1/LINC02103, AL136418.1). Conclusions The identified genes/loci for PF and age-related traits suggest their underlying shared genetic effects, which can explain part of their phenotypic correlations. Integration of gene expression and genomic annotation data shows enrichment of our genetic variants in lung, blood, adipose, pancreas, and muscles, among others. Our findings highlight the critical roles of identified gene/locus in systemic inflammation, glucose metabolism, strength performance, PF, and pulmonary disease, which are involved in accelerated biological aging.
    Type of Medium: Online Resource
    ISSN: 1079-5006 , 1758-535X
    URL: Article
    DOI: 10.1093/gerona/glac046
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 10
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    Allele-specific variation at APOE increases nonalcoholic fatty liver disease and obesity but decreases risk of Alzheimer’s disease and myocardial infarction
    Oxford University Press (OUP) ; 2021
    In:  Human Molecular Genetics Vol. 30, No. 15 ( 2021-07-09), p. 1443-1456
    Details
    In: Human Molecular Genetics, Oxford University Press (OUP), Vol. 30, No. 15 ( 2021-07-09), p. 1443-1456
    Abstract: Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease and is highly correlated with metabolic disease. NAFLD results from environmental exposures acting on a susceptible polygenic background. This study performed the largest multiethnic investigation of exonic variation associated with NAFLD and correlated metabolic traits and diseases. An exome array meta-analysis was carried out among eight multiethnic population-based cohorts (n = 16 492) with computed tomography (CT) measured hepatic steatosis. A fixed effects meta-analysis identified five exome-wide significant loci (P  & lt; 5.30 × 10−7); including a novel signal near TOMM40/APOE. Joint analysis of TOMM40/APOE variants revealed the TOMM40 signal was attributed to APOE rs429358-T; APOE rs7412 was not associated with liver attenuation. Moreover, rs429358-T was associated with higher serum alanine aminotransferase, liver steatosis, cirrhosis, triglycerides and obesity; as well as, lower cholesterol and decreased risk of myocardial infarction and Alzheimer’s disease (AD) in phenome-wide association analyses in the Michigan Genomics Initiative, United Kingdom Biobank and/or public datasets. These results implicate APOE in imaging-based identification of NAFLD. This association may or may not translate to nonalcoholic steatohepatitis; however, these results indicate a significant association with advanced liver disease and hepatic cirrhosis. These findings highlight allelic heterogeneity at the APOE locus and demonstrate an inverse link between NAFLD and AD at the exome level in the largest analysis to date.
    Type of Medium: Online Resource
    ISSN: 0964-6906 , 1460-2083
    URL: Article
    DOI: 10.1093/hmg/ddab096
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 1474816-2
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