Publications by authors named "Tamara Harris"

978 Publications

Exploratory assessment of pineal gland volume, composition, and urinary 6-sulfatoxymelatonin levels on prostate cancer risk.

Prostate 2021 Jun 16;81(8):487-496. Epub 2021 Apr 16.

Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA.

Introduction: Melatonin levels are partially driven by the parenchyma volume of the pineal gland. Low urinary levels of 6-sulfatoxymelatonin have been associated with increased risk of advanced prostate cancer, but the relationship between pineal gland volume and composition and prostate cancer risk has not been examined.

Materials And Methods: We utilized data from 864 men from the AGES-Reykjavik Study with complete pineal gland volumes and urinary 6-sulfatoxymelatonin measurements. Pineal parenchyma, calcification, and cyst volumes were calculated from brain magnetic resonance imaging. Levels of 6-sulfatoxymelatonin were assayed from prediagnostic urine samples. We calculated Pearson correlation coefficients between parenchyma volume and urinary 6-sulfatoxymelatonin levels. We used Cox proportional hazards regression to calculate multivariable hazard ratios (HRs) and 95% confidence intervals (95% CIs) comparing prostate cancer risk across parenchyma volume tertiles and across categories factoring in parenchyma volume, gland composition, and urinary 6-sulfatoxymelatonin level.

Results: Parenchyma volume was moderately correlated with urinary 6-sulfatoxymelatonin level (r = .24; p < .01). There was no statistically significant association between parenchyma volume tertile and prostate cancer risk. Men with high parenchyma volume, pineal cysts and calcifications, and low urinary 6-sulfatoxymelatonin levels had almost twice the risk of total prostate cancer as men with low parenchyma volume, no pineal calcifications or cysts, and low urinary 6-sulfatoxymelatonin levels (HR: 1.98; 95% CI: 1.02, 3.84; p: .04).

Conclusions: Although parenchyma volume is not associated with prostate cancer risk, pineal gland composition and other circadian dynamics may influence risk for prostate cancer. Additional studies are needed to examine the interplay of pineal gland volume, composition, and melatonin levels on prostate cancer risk.
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http://dx.doi.org/10.1002/pros.24130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8194005PMC
June 2021

Sex-specific 25-hydroxyvitamin D threshold concentrations for functional outcomes in older adults: PRoject on Optimal VItamin D in Older adults (PROVIDO).

Am J Clin Nutr 2021 07;114(1):16-28

California Pacific Medical Center Research Institute, San Francisco, CA, USA.

Background: Threshold serum 25-hydroxyvitamin D [25(OH)D] concentrations for extraskeletal outcomes are uncertain and could differ from recommendations (20-30 ng/mL) for skeletal health.

Objectives: We aimed to identify and validate sex-specific threshold 25(OH)D concentrations for older adults' physical function.

Methods: Using 5 large prospective, population-based studies-Age, Gene/Environment Susceptibility-Reykjavik (n = 4858, Iceland); Health, Aging, and Body Composition (n = 2494, United States); Invecchiare in Chianti (n = 873, Italy); Osteoporotic Fractures in Men (n = 2301, United States); and Study of Osteoporotic Fractures (n = 5862, United States)-we assessed 16,388 community-dwelling adults (10,376 women, 6012 men) aged ≥65 y. We analyzed 25(OH)D concentrations with the primary outcome (incident slow gait: women <0.8 m/s; men <0.825 m/s) and secondary outcomes (gait speed, incident self-reported mobility, and stair climb impairment) at median 3.0-y follow-up. We identified sex-specific 25(OH)D thresholds that best discriminated incident slow gait using machine learning in training data (2/3 cohort-stratified random sample) and validated using the remaining (validation) data and secondary outcomes.

Results: Mean age in the cohorts ranged from 74.4 to 76.5 y in women and from 73.3 to 76.6 y in men. Overall, 1112/6123 women (18.2%) and 494/3937 men (12.5%) experienced incident slow gait, 1098/7011 women (15.7%) and 474/3962 men (12.0%) experienced incident mobility impairment, and 1044/6941 women (15.0%) and 432/3993 men (10.8%) experienced incident stair climb impairment. Slow gait was best discriminated by 25(OH)D <24.0 ng/mL compared with 25(OH)D ≥24.0 ng/mL in women (RR: 1.29; 95% CI: 1.10, 1.50) and 25(OH)D <21.0 ng/mL compared with 25(OH)D ≥21.0 ng/mL in men (RR: 1.43; 95% CI: 1.01, 2.02). Most associations between 25(OH)D and secondary outcomes were modest; estimates were similar between validation and training datasets.

Conclusions: Empirically identified and validated sex-specific threshold 25(OH)D concentrations for physical function for older adults, 24.0 ng/mL for women and 21.0 ng/mL for men, may inform candidate reference concentrations or the design of vitamin D intervention trials.
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http://dx.doi.org/10.1093/ajcn/nqab025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246604PMC
July 2021

Association between 25-Hydroxyvitamin D and Metabolic Syndrome in Older Adults: The Health, Aging and Body Composition Study.

Int J Endocrinol 2021 13;2021:6671823. Epub 2021 Mar 13.

For the Health ABC Study, Sticht Center on Aging, Wake Forest School of Medicine, Winston-Salem, NC, USA.

Objective: Low 25-hydroxyvitamin D (25[OH]D) levels and metabolic syndrome (MetS) are prevalent among older adults; however, longitudinal studies examining 25(OH)D status and MetS are lacking. We explore the association of 25(OH)D levels with prevalent and incident MetS in white and black older adults. . A total of 1620 white and 1016 black participants aged 70-79 years from the Health ABC cohort with measured 25(OH)D levels and data on MetS and covariates of interest were examined. The association between 25(OH)D levels and prevalent MetS at baseline and incident MetS at 6-year follow-up was examined in whites and blacks separately using logistic regression adjusting for demographics, lifestyle factors, and renal function.

Results: At baseline, 635 (39%) white and 363 (36%) black participants had prevalent MetS. In whites, low 25(OH)D levels were associated with prevalent MetS (adjusted OR (95% CI), 1.85 (1.47, 2.34)) and 1.96 (1.46, 2.63) for 25(OH)D of 20-<30 and <20 vs. ≥30 ng/ml, respectively). The association was attenuated after adjustment for BMI but remained significant. No association was found between 25(OH)D levels and prevalent MetS in blacks. Among those without MetS at baseline (765 whites, 427 blacks), 150 (20%) whites and 87 (20%) blacks had developed MetS at 6-year follow-up. However, 25(OH)D levels were not associated with incident MetS in whites or blacks.

Conclusion: In older adults, low 25(OH)D levels were associated with increased odds of prevalent MetS in whites but not in blacks. No association was observed between 25(OH)D levels and incident MetS in either whites or blacks.
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http://dx.doi.org/10.1155/2021/6671823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7981173PMC
March 2021

Accelerated decline in quadriceps area and Timed Up and Go test performance are associated with hip fracture risk in older adults with impaired kidney function.

Exp Gerontol 2021 07 16;149:111314. Epub 2021 Mar 16.

National Institute on Aging, Intramural Research Program, Laboratory of Epidemiology and Population Sciences, Bethesda, MD, USA.

Objective: This study aimed to examine whether an accelerated decline in quadriceps cross-sectional area (CSA), attenuation (a surrogate of quality), and strength, as well as lower limb muscular function, are associated with hip fractures in older adults with impaired kidney function.

Design: Prospective population-based study.

Setting: Community-dwelling old population in Reykjavik, Iceland.

Subjects: A total of 875 older adults (mean baseline age 76 years) from the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study with impaired kidney function.

Methods: Quadriceps CSA and density were determined using computed tomography (CT), knee extension strength was measured with an isometric dynamometer chair, and muscular function was assessed using the Timed Up and Go (TUG) test. All muscle-related measurements were assessed twice over a mean follow-up of 5.2 years. Data on hip fracture incidence was obtained from medical records during a maximum of 8.4 years of follow-up time.

Results: Fully adjusted cox-proportional hazard regression models showed that a faster decline in quadriceps CSA and TUG test performance were significantly associated with increased hip fracture risk (HR = 1.55, 95% CI = 1.02-2.36, and HR = 1.80, 95% CI = 1.19-2.72, respectively). A faster decrease in quadriceps density and isometric knee extension strength were not associated with fracture risk.

Conclusions: Accelerated decline in CT-derived quadriceps CSA and muscular function, as measured by the TUG test's performance, are predictive of hip fracture risk in older adults with impaired kidney function. TUG test is a simple measure and easily included in routine medical examinations, compared to CT scans, which seems to be useful for identifying a subgroup of individuals with high risk of fracture.
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http://dx.doi.org/10.1016/j.exger.2021.111314DOI Listing
July 2021

Computed tomography-based skeletal muscle and adipose tissue attenuation: Variations by age, sex, and muscle.

Exp Gerontol 2021 07 10;149:111306. Epub 2021 Mar 10.

Laboratory of Epidemiology and Population Science, Intramural Research Program, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.

Objective: This study aimed to investigate how skeletal muscle attenuation and adipose tissue (AT) attenuation of the quadriceps, hamstrings, paraspinal muscle groups and the psoas muscle vary according to the targeted muscles, sex, and age.

Design: Population-based cross-sectional study.

Setting: Community-dwelling old population in Reykjavik, Iceland.

Subjects: A total of 5331 older adults (42.8% women), aged 66-96 years from the Age, Gene/Environment Susceptibility (AGES)- Reykjavik Study, who participated in the baseline visit (between 2002 and 2006) and had valid thigh and abdominal computed tomography (CT) scans were studied.

Methods: Muscle attenuation and AT attenuation of the quadriceps, hamstrings, paraspinal muscle groups and the psoas muscle were determined using CT. Linear mixed model analysis of variance was performed for each sex, with skeletal muscle or AT attenuation as the dependent variable.

Results: Muscle attenuation decreased, and AT attenuation increased with age in both sexes, and these differences were specific for each muscle, although not in all age groups. Age-related differences in muscle and AT attenuation varied with specific muscle. In general, for both sexes, skeletal muscle attenuation of the hamstrings declined more than average with age. Men and women displayed a different pattern in the age differences in AT attenuation for each muscle.

Conclusions: Our data support the hypotheses that skeletal muscle attenuation decreases, and AT attenuation increases with aging. In addition, our data add new evidence, supporting that age-related differences in skeletal muscle and AT attenuation vary between muscles.
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http://dx.doi.org/10.1016/j.exger.2021.111306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096682PMC
July 2021

Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry.

Am J Hum Genet 2021 04 12;108(4):564-582. Epub 2021 Mar 12.

The Charles R. Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.
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http://dx.doi.org/10.1016/j.ajhg.2021.02.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059339PMC
April 2021

Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability.

Nat Commun 2021 01 5;12(1):24. Epub 2021 Jan 5.

Department of Biostatistics and Data Science, Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA.

Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
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http://dx.doi.org/10.1038/s41467-020-19366-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785747PMC
January 2021

Serum FSH Is Associated With BMD, Bone Marrow Adiposity, and Body Composition in the AGES-Reykjavik Study of Older Adults.

J Clin Endocrinol Metab 2021 03;106(3):e1156-e1169

Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA.

Context: Follicle-stimulating hormone (FSH) concentrations increase during the perimenopausal transition and remain high after menopause. Loss of bone mineral density (BMD) and gain of bone marrow adiposity (BMA) and body fat mass also occur during this time. In mice, blocking the action of FSH increases bone mass and decreases fat mass.

Objective: To investigate the associations between endogenous FSH levels and BMD, BMA, and body composition in older adults, independent of estradiol and testosterone levels.

Design, Setting, And Participants: Older adults from the AGES-Reykjavik Study, an observational cohort study.

Main Outcome Measures: Areal BMD, total body fat, and lean mass were measured with dual-energy x-ray absorptiometry. Lumbar vertebral BMA was measured by 1H-magnetic resonance spectroscopy. Volumetric BMD and visceral and subcutaneous adipose tissue (VAT, SAT) areas were measured with quantitative computed tomography. The least squares means procedure was used to determine sex hormone-adjusted associations between quartiles of serum FSH and BMD, BMA, and body composition.

Results: In women (N = 238, mean age 81 years), those in the highest FSH quartile, compared with the lowest quartile, had lower adjusted mean spine integral BMD (-8.6%), lower spine compressive strength index (-34.8%), higher BMA (+8.4%), lower weight (-8.4%), lower VAT (-17.6%), lower lean mass (-6.1%), and lower fat mass (-11.9%) (all P < 0.05). In men, FSH level was not associated with any outcome.

Conclusions: Older postmenopausal women with higher FSH levels have higher BMA, but lower BMD and lower fat and lean mass, independent of estradiol and testosterone levels. Longitudinal studies are needed to better understand the underlying mechanisms.
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http://dx.doi.org/10.1210/clinem/dgaa922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947831PMC
March 2021

A Meta-Analysis of the Transferability of Bone Mineral Density Genetic Loci Associations From European to African Ancestry Populations.

J Bone Miner Res 2021 03 18;36(3):469-479. Epub 2020 Dec 18.

Hinda and Arthur Marcus Institute for Aging Research, Hebrew SeniorLife, Boston, MA, USA.

Genetic studies of bone mineral density (BMD) largely have been conducted in European populations. We therefore conducted a meta-analysis of six independent African ancestry cohorts to determine whether previously reported BMD loci identified in European populations were transferable to African ancestry populations. We included nearly 5000 individuals with both genetic data and assessments of BMD. Genotype imputation was conducted using the 1000G reference panel. We assessed single-nucleotide polymorphism (SNP) associations with femoral neck and lumbar spine BMD in each cohort separately, then combined results in fixed effects (or random effects if study heterogeneity was high, I index >60) inverse variance weighted meta-analyses. In secondary analyses, we conducted locus-based analyses of rare variants using SKAT-O. Mean age ranged from 12 to 68 years. One cohort included only men and another cohort included only women; the proportion of women in the other four cohorts ranged from 52% to 63%. Of 56 BMD loci tested, one locus, 6q25 (C6orf97, p = 8.87 × 10 ), was associated with lumbar spine BMD and two loci, 7q21 (SLC25A13, p = 2.84 × 10 ) and 7q31 (WNT16, p = 2.96 × 10 ), were associated with femoral neck BMD. Effects were in the same direction as previously reported in European ancestry studies and met a Bonferroni-adjusted p value threshold, the criteria for transferability to African ancestry populations. We also found associations that met locus-specific Bonferroni-adjusted p value thresholds in 11q13 (LRP5, p < 2.23 × 10 ), 11q14 (DCDC5, p < 5.35 × 10 ), and 17p13 (SMG6, p < 6.78 × 10 ) that were not tagged by European ancestry index SNPs. Rare single-nucleotide variants in AKAP11 (p = 2.32 × 10 ), MBL2 (p = 4.09 × 10 ), MEPE (p = 3.15 × 10 ), SLC25A13 (p = 3.03 × 10 ), STARD3NL (p = 3.35 × 10 ), and TNFRSF11A (p = 3.18 × 10 ) were also associated with BMD. The majority of known BMD loci were not transferable. Larger genetic studies of BMD in African ancestry populations will be needed to overcome limitations in statistical power and to identify both other loci that are transferable across populations and novel population-specific variants. © 2020 American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353846PMC
March 2021

Jump power, leg press power, leg strength and grip strength differentially associated with physical performance: The Developmental Epidemiologic Cohort Study (DECOS).

Exp Gerontol 2021 03 24;145:111172. Epub 2020 Nov 24.

Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address:

Background: Weight-bearing jump tests that measure lower-extremity muscle power may be more strongly related to physical performance measures vs. non-weight-bearing leg press power, leg press strength and grip strength. We investigated if multiple muscle function measures differentially related to standard physical performance measures.

Materials/methods: In the Developmental Epidemiologic Cohort Study (DECOS; N = 68; age 78.5 ± 5.5 years; 57% women; 7% minorities), muscle function measures included power in Watts/kg (functional, weight-bearing: jump; mechanical: Nottingham power rig; Keiser pneumatic leg press) and strength in kg/kg body weight (Keiser pneumatic leg press; hand-held dynamometry). Physical performance outcomes included 6 m usual gait speed (m/s), usual-paced 400 m walk time (seconds), and 5-repeated chair stands speed (stands/s).

Results: Women (N = 31; 79.8 ± 5.0 years) had lower muscle function and slower gait speed compared to men (N = 25; 78.7 ± 6.6 years), though similar 400 m walk time and chair stands speed. In partial Pearson correlations adjusted for age, sex, race and height, muscle function measures were moderately to strongly correlated with each other (all p < 0.05), though the individual correlations varied. In multiple regression analyses, each muscle function measure was statistically associated with all physical performance outcomes in models adjusted for age, sex, race, height, self-reported diabetes, self-reported peripheral vascular disease and self-reported pain in legs/feet (all p < 0.05). Jump power (β = 0.75) and grip strength (β = 0.71) had higher magnitudes of association with faster gait speed than lower-extremity power and strength measures (β range: 0.32 to 0.58). Jump power (β = 0.56) had a slightly lower magnitude of association with faster 400 m walk time vs. Keiser power (β = 0.61), and a higher magnitude of association vs. Nottingham power, Keiser strength and grip strength (β range: 0.41 to 0.47). Jump power (β = 0.38) had a lower magnitude of association with chair stands speed than any other power or strength measures (β range: 0.50 to 0.65).

Conclusions: Jump power/kg and grip strength/kg may be more strongly related to faster gait speed, a standard measure of physical function and vital sign related to disability and mortality in older adults, compared to leg press power/strength. However, jump power/kg had a similar magnitude of association with 400 m walk time as Keiser power/kg and a lower magnitude of association with faster chair stands speed than the other muscle function measures. Importantly, choice of muscle function measures should carefully reflect the study focus and methodologic considerations, including population.
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http://dx.doi.org/10.1016/j.exger.2020.111172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855418PMC
March 2021

A Noncoding Variant Near PPP1R3B Promotes Liver Glycogen Storage and MetS, but Protects Against Myocardial Infarction.

J Clin Endocrinol Metab 2021 01;106(2):372-387

Brigham and Women's Hospital, Havard University, Boston, MA, USA.

Context: Glycogen storage diseases are rare. Increased glycogen in the liver results in increased attenuation.

Objective: Investigate the association and function of a noncoding region associated with liver attenuation but not histologic nonalcoholic fatty liver disease.

Design: Genetics of Obesity-associated Liver Disease Consortium.

Setting: Population-based.

Main Outcome: Computed tomography measured liver attenuation.

Results: Carriers of rs4841132-A (frequency 2%-19%) do not show increased hepatic steatosis; they have increased liver attenuation indicative of increased glycogen deposition. rs4841132 falls in a noncoding RNA LOC157273 ~190 kb upstream of PPP1R3B. We demonstrate that rs4841132-A increases PPP1R3B through a cis genetic effect. Using CRISPR/Cas9 we engineered a 105-bp deletion including rs4841132-A in human hepatocarcinoma cells that increases PPP1R3B, decreases LOC157273, and increases glycogen perfectly mirroring the human disease. Overexpression of PPP1R3B or knockdown of LOC157273 increased glycogen but did not result in decreased LOC157273 or increased PPP1R3B, respectively, suggesting that the effects may not all occur via affecting RNA levels. Based on electronic health record (EHR) data, rs4841132-A associates with all components of the metabolic syndrome (MetS). However, rs4841132-A associated with decreased low-density lipoprotein (LDL) cholesterol and risk for myocardial infarction (MI). A metabolic signature for rs4841132-A includes increased glycine, lactate, triglycerides, and decreased acetoacetate and beta-hydroxybutyrate.

Conclusions: These results show that rs4841132-A promotes a hepatic glycogen storage disease by increasing PPP1R3B and decreasing LOC157273. rs4841132-A promotes glycogen accumulation and development of MetS but lowers LDL cholesterol and risk for MI. These results suggest that elevated hepatic glycogen is one cause of MetS that does not invariably promote MI.
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http://dx.doi.org/10.1210/clinem/dgaa855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823249PMC
January 2021

Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals.

Nat Genet 2020 12 23;52(12):1314-1332. Epub 2020 Nov 23.

Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
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http://dx.doi.org/10.1038/s41588-020-00713-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610439PMC
December 2020

Genetic loci associated with prevalent and incident myocardial infarction and coronary heart disease in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.

PLoS One 2020 13;15(11):e0230035. Epub 2020 Nov 13.

The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California, United States of America.

Background: Genome-wide association studies have identified multiple genomic loci associated with coronary artery disease, but most are common variants in non-coding regions that provide limited information on causal genes and etiology of the disease. To overcome the limited scope that common variants provide, we focused our investigation on low-frequency and rare sequence variations primarily residing in coding regions of the genome.

Methods And Results: Using samples of individuals of European ancestry from ten cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, both cross-sectional and prospective analyses were conducted to examine associations between genetic variants and myocardial infarction (MI), coronary heart disease (CHD), and all-cause mortality following these events. For prevalent events, a total of 27,349 participants of European ancestry, including 1831 prevalent MI cases and 2518 prevalent CHD cases were used. For incident cases, a total of 55,736 participants of European ancestry were included (3,031 incident MI cases and 5,425 incident CHD cases). There were 1,860 all-cause deaths among the 3,751 MI and CHD cases from six cohorts that contributed to the analysis of all-cause mortality. Single variant and gene-based analyses were performed separately in each cohort and then meta-analyzed for each outcome. A low-frequency intronic variant (rs988583) in PLCL1 was significantly associated with prevalent MI (OR = 1.80, 95% confidence interval: 1.43, 2.27; P = 7.12 × 10-7). We conducted gene-based burden tests for genes with a cumulative minor allele count (cMAC) ≥ 5 and variants with minor allele frequency (MAF) < 5%. TMPRSS5 and LDLRAD1 were significantly associated with prevalent MI and CHD, respectively, and RC3H2 and ANGPTL4 were significantly associated with incident MI and CHD, respectively. No loci were significantly associated with all-cause mortality following a MI or CHD event.

Conclusion: This study identified one known locus (ANGPTL4) and four new loci (PLCL1, RC3H2, TMPRSS5, and LDLRAD1) associated with cardiovascular disease risk that warrant further investigation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0230035PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665790PMC
December 2020

Validation of a description of sarcopenic obesity defined as excess adiposity and low lean mass relative to adiposity.

J Cachexia Sarcopenia Muscle 2020 12 15;11(6):1580-1589. Epub 2020 Sep 15.

Division of Endocrinology and Diabetes, Golisano Children's Hospital, University of Rochester, Rochester, NY, USA.

Background: This study aims to assess the construct validity of a body composition-defined definition of sarcopenic obesity based on low appendicular lean mass relative to fat mass (ALMI ) and high fat mass index (FMI) and to compare with an alternative definition using appendicular lean mass index (ALMI) and percent body fat (%BF).

Methods: This is a secondary analysis of two cohort studies: the National Health and Examination Survey (NHANES) and the Health, Aging, and Body Composition study (Health ABC). Sarcopenic obesity was defined as low ALMI combined with high FMI and was compared with a widely used definition based on ALMI and %BF cut-points. Body composition Z-scores, self-reported disability, physical functioning, and incident disability were compared across body composition categories using linear and logistic regression and Cox proportional hazards models.

Results: Among 14, 850 participants from NHANES, patients with sarcopenic obesity defined by low ALMI and high FMI (ALMI -FMI) had above-average FMI Z-scores [mean (standard deviation): 1.00 (0.72)]. In contrast, those with sarcopenic obesity based on low ALMI and high %BF (ALMI-%BF) had below-average FMI Z-scores. A similar pattern was observed for 2846 participants from Health ABC. Participants with sarcopenic obesity based on ALMI -FMI had a greater number of disabilities, worse physical function, and a greater risk of incident disability compared with those defined based on ALMI-%BF.

Conclusions: Body composition-defined measures of sarcopenic obesity defined as excess adiposity and lower-than-expected ALMI relative to FMI are associated with functional deficits and incident disability and overcome the limitations of using %BF in estimating obesity in this context.
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http://dx.doi.org/10.1002/jcsm.12613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749601PMC
December 2020

Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity.

Diabetes 2020 12 11;69(12):2806-2818. Epub 2020 Sep 11.

Department of Biostatistics, Boston University School of Public Health, Boston, MA.

Leptin influences food intake by informing the brain about the status of body fat stores. Rare mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in , , , and , and one intergenic variant near The missense variant Val94Met (rs17151919) in was common in individuals of African ancestry only, and its association with lower leptin concentrations was specific to this ancestry ( = 2 × 10, = 3,901). Using in vitro analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting that leptin regulates early adiposity.
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http://dx.doi.org/10.2337/db20-0070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679778PMC
December 2020

Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction.

Nat Commun 2020 05 21;11(1):2542. Epub 2020 May 21.

Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.
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http://dx.doi.org/10.1038/s41467-020-15706-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242331PMC
May 2020

Plasma Soluble αKlotho, Serum Fibroblast Growth Factor 23, and Mobility Disability in Community-Dwelling Older Adults.

J Endocr Soc 2020 May 30;4(5):bvz032. Epub 2020 Apr 30.

Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania.

Context: αKlotho is a hormone and co-receptor for fibroblast growth factor 23 (FGF23), a hormone that downregulates active vitamin D synthesis and promotes phosphate excretion. Low αKlotho and high FGF23 occur in chronic kidney disease (CKD).

Objective: We aimed to assess the relationships of αKlotho and FGF23 with mobility disability in community-dwelling older adults.

Design And Setting: We estimated associations of plasma-soluble αKlotho and serum FGF23 concentrations with mobility disability over 6 years. Additional analyses was stratified by CKD.

Participants: Participants included 2751 adults (25.0% with CKD), aged 71 to 80 years, from the 1998 to 1999 Health, Aging, and Body Composition Study visit.

Main Outcome Measures: Walking disability and stair climb disability were defined as self-reported "a lot of difficulty" or an inability to walk a quarter mile and climb 10 stairs, respectively.

Results: Median (interquartile range [IQR]) serum FGF23 and plasma soluble αKlotho concentrations were 46.6 (36.7, 60.2) pg/mL and 630.4 (478.4, 816.0) pg/mL, respectively. After adjustment, higher αKlotho concentrations were associated with lower walking disability rates (Rate Ratio [RR] highest vs. lowest tertile = 0.74; 95% confidence interval l [CI] = 0.62, 0.89;  = 0.003). Higher FGF23 concentrations were associated with higher walking disability rates (RR highest vs. lowest tertile = 1.24; 95%CI = 1.03, 1.50;  = 0.005). Overall, higher αKlotho combined with lower FGF23 was associated with the lowest walking disability rates ( for interaction = 0.023). Stair climb disability findings were inconsistent. No interactions with CKD were statistically significant ( for interaction > 0.10).

Conclusions: Higher plasma soluble αKlotho and lower serum FGF23 concentrations were associated with lower walking disability rates in community-dwelling older adults, particularly those without CKD.
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http://dx.doi.org/10.1210/jendso/bvz032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7209777PMC
May 2020

Smoking-by-genotype interaction in type 2 diabetes risk and fasting glucose.

PLoS One 2020 7;15(5):e0230815. Epub 2020 May 7.

Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, United States of America.

Smoking is a potentially causal behavioral risk factor for type 2 diabetes (T2D), but not all smokers develop T2D. It is unknown whether genetic factors partially explain this variation. We performed genome-environment-wide interaction studies to identify loci exhibiting potential interaction with baseline smoking status (ever vs. never) on incident T2D and fasting glucose (FG). Analyses were performed in participants of European (EA) and African ancestry (AA) separately. Discovery analyses were conducted using genotype data from the 50,000-single-nucleotide polymorphism (SNP) ITMAT-Broad-CARe (IBC) array in 5 cohorts from from the Candidate Gene Association Resource Consortium (n = 23,189). Replication was performed in up to 16 studies from the Cohorts for Heart Aging Research in Genomic Epidemiology Consortium (n = 74,584). In meta-analysis of discovery and replication estimates, 5 SNPs met at least one criterion for potential interaction with smoking on incident T2D at p<1x10-7 (adjusted for multiple hypothesis-testing with the IBC array). Two SNPs had significant joint effects in the overall model and significant main effects only in one smoking stratum: rs140637 (FBN1) in AA individuals had a significant main effect only among smokers, and rs1444261 (closest gene C2orf63) in EA individuals had a significant main effect only among nonsmokers. Three additional SNPs were identified as having potential interaction by exhibiting a significant main effects only in smokers: rs1801232 (CUBN) in AA individuals, rs12243326 (TCF7L2) in EA individuals, and rs4132670 (TCF7L2) in EA individuals. No SNP met significance for potential interaction with smoking on baseline FG. The identification of these loci provides evidence for genetic interactions with smoking exposure that may explain some of the heterogeneity in the association between smoking and T2D.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0230815PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205201PMC
August 2020

Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci.

Mol Psychiatry 2021 Jun 5;26(6):2111-2125. Epub 2020 May 5.

Health Disparities Research Section, Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA.

Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.
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http://dx.doi.org/10.1038/s41380-020-0719-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641978PMC
June 2021

A Metabolite Composite Score Attenuated a Substantial Portion of the Higher Mortality Risk Associated With Frailty Among Community-Dwelling Older Adults.

J Gerontol A Biol Sci Med Sci 2021 01;76(2):378-384

Department of Epidemiology, University of Pittsburgh, Pennsylvania.

Background: Frailty is more prevalent among black versus white older Americans. We previously identified 37 metabolites associated with the vigor to frailty spectrum using the Scale of Aging Vigor in Epidemiology (SAVE) among older black men from the Health, Aging, and Body Composition (Health ABC) study. Here, we sought to develop a metabolite composite score based on the 37 SAVE-associated metabolites and determine whether the composite score predicts mortality and whether it attenuates the association between frailty and mortality among older black men.

Methods: Plasma metabolites were measured using liquid chromatography-mass spectrometry. Most of the 37 metabolites were organic acids/derivatives or lipids. Metabolites were ranked into tertiles: tertiles associated with more vigorous SAVE scores were scored 0, mid-tertiles were scored 1, and tertiles associated with frailer SAVE scores were scored 2. Composite scores were the sum of metabolite tertile scores. We examined mortality associations using Cox regression. Percent attenuation estimated the extent to which metabolites attenuated the association between frailty and mortality.

Results: One standard deviation frailer SAVE was associated with 30% higher mortality, adjusting for age and site (p = .0002); this association was attenuated by 56% after additionally adjusting for the metabolite composite score. In this model, one standard deviation higher metabolite composite score was associated with 46% higher mortality (p < .0001). Metabolite composite scores also predicted mortality (p = .045) in a validation sample of 120 older adults (40% men, 90% white).

Conclusion: These metabolites may provide a deeper characterization of the higher mortality that is associated with frailty among older adults.
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http://dx.doi.org/10.1093/gerona/glaa112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812434PMC
January 2021

Olfaction and Changes in Body Composition in a Large Cohort of Older U.S. Adults.

J Gerontol A Biol Sci Med Sci 2020 11;75(12):2434-2440

Department of Epidemiology and Biostatistics, College of Human Medicine, Michigan State University, East Lansing.

Background: Poor sense of smell in older adults may lead to weight loss, which may further contribute to various adverse health outcomes. However, empirical prospective evidence is lacking. We aimed to longitudinally assess whether poor olfaction is associated with changes in body composition among older adults.

Methods: A total of 2,390 participants from the Health ABC Study had their olfaction assessed using the Brief Smell Identification Test in 1999-2000. Based on the test score, olfaction was defined as poor (0-8), moderate (9-10), or good (11-12). Total body mass, lean mass, and fat mass were measured by dual-energy X-ray absorptiometry annually or biennially from 1999 to 2007.

Results: At baseline, compared to participants with good olfaction, those with poor olfaction weighed on average 1.67 kg less (95% CI: -2.92, -0.42) in total mass, 0.53 kg less (95% CI: -1.08, 0.02) in lean mass, and 1.14 kg less (95% CI: -1.96, -0.31) in fat mass. In longitudinal analyses, compared to participants with good olfaction, those with poor olfaction had a greater annual decline in both total mass (-234 g, 95% CI: -442, -26) and lean mass (-139 g, 95% CI: -236, -43). They also tended to have a greater annual loss of fat mass (-113 g, 95% CI: -285, 59), but the difference was not statistically significant.

Conclusions: Our results indicate poor olfaction is associated with lower body weight and greater weight loss in older adults. It is imperative for future studies to investigate potential underlying mechanisms and associated adverse health consequences.
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http://dx.doi.org/10.1093/gerona/glaa085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662158PMC
November 2020

Childhood overweight and obesity and the risk of depression across the lifespan.

BMC Pediatr 2020 01 21;20(1):25. Epub 2020 Jan 21.

Unit for Nutrition Research, Landspitali, The National University Hospital of Iceland and Faculty of Food Science and Nutrition, School of Health Sciences, University of Iceland, Eiriksgata 29, 101, Reykjavik, Iceland.

Background: Obesity has been longitudinally associated with depression but only few studies take a life course approach. This longitudinal study investigates whether being overweight or obese at age 8 and 13 years is associated with depressive symptoms more than 60 years later and whether this association is independent of late-life body mass index (BMI). We also investigated the association of being overweight/obese at age 8 or 13 years with ever having major depressive disorder (lifetime MDD).

Method: This analysis is based on a sub-sample of 889 AGES-Reykjavik participants with measured BMI data from early life. Late-life depressive symptoms were measured with the Geriatric Depression Scale (GDS) and lifetime MDD was assessed at late-life using the Mini International Neuropsychiatric Interview. Logistic regression analysis was used to estimate the relationships between BMI (continuous and categorical) at age 8 or 13 years, and late-life depressive symptoms (measured as GDS ≥ 5) or lifetime MDD, adjusted for sex, education, physical activity, smoking status and alcohol use. In a separate model, additional adjustments were made for late-life BMI.

Results: One hundred and one subjects (11%) had depressive symptoms at late-life (GDS ≥ 5), and 39 subjects (4.4%) had lifetime MDD. Being overweight or obese at age 8 or 13 years was not associated with higher depressive symptoms during late-life, irrespective of late-life BMI. Being overweight or obese at age 8 years, but not age 13 years was associated with an increased risk of lifetime MDD (Odds Ratio (OR) (95% confidence interval [CI]) for age 8 = 4.03[1.16-13.96]P = 0.03 and age 13 = 2.65[0.69-10.26] P = 0.16, respectively).

Conclusion: Being overweight in childhood was associated with increased odds of lifetime MDD, although the magnitude of the risk is uncertain given the small numbers of participants with lifetime MDD. No clear association was observed between childhood and adolescent overweight/obesity and late-life depressive symptoms irrespective of late life BMI.
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http://dx.doi.org/10.1186/s12887-020-1930-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971945PMC
January 2020

Associations between novel jump test measures, grip strength, and physical performance: the Osteoporotic Fractures in Men (MrOS) Study.

Aging Clin Exp Res 2020 Apr 18;32(4):587-595. Epub 2019 Dec 18.

Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, 130 N. Bellefield Ave., Suite 300, Pittsburgh, PA, 15213, USA.

Background/aims: Weight-bearing jump tests measure lower extremity muscle power, velocity, and force, and may be more strongly related to physical performance than grip strength. However, these relationships are not well described in older adults.

Methods: Participants were 1242 older men (mean age 84 ± 4 years) in the Osteoporotic Fractures in Men (MrOS) Study. Jump peak power (Watts/kg body weight), force (Newton/kg body weight) at peak power, and velocity (m/s) at peak power were measured by jump tests on a force plate. Grip strength (kg/kg body weight) was assessed by hand-held dynamometry. Physical performance included 400 m walk time (s), 6 m usual gait speed (m/s), and 5-repeated chair stands speed (#/s).

Results: In adjusted Pearson correlations, power/kg and velocity moderately correlated with all performance measures (range r = 0.41-0.51; all p < 0.001), while correlations for force/kg and grip strength/kg were weaker (range r = 0.20-0.33; all p < 0.001). Grip strength/kg moderately correlated with power/kg (r = 0.44; p < 0.001) but not velocity or force/kg. In adjusted linear regression with standardized βs, 1 SD lower power/kg was associated with worse: 400 m walk time (β = 0.47), gait speed (β = 0.42), and chair stands speed (β = 0.43) (all p < 0.05). Associations with velocity were similar (400 m walk time: β = 0.42; gait speed: β = 0.38; chair stands speed: β = 0.37; all p < 0.05). Force/kg and grip strength/kg were more weakly associated with performance (range β = 0.18-0.28; all p < 0.05).

Conclusions/discussion: Jump power and velocity had stronger associations with physical performance than jump force or grip strength. This suggests lower extremity power and velocity may be more strongly related to physical performance than lower extremity force or upper extremity strength in older men.
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http://dx.doi.org/10.1007/s40520-019-01421-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716274PMC
April 2020

Accelerometry data in health research: challenges and opportunities.

Stat Biosci 2019 Jul 12;11(2):210-237. Epub 2019 Jan 12.

Center on Aging and Health, Division of Geriatric Medicine and Gerontology, Department of Medicine, School of Medicine, Johns Hopkins University,

Wearable accelerometers provide detailed, objective, and continuous measurements of physical activity (PA). Recent advances in technology and the decreasing cost of wearable devices led to an explosion in the popularity of wearable technology in health research. An ever-increasing number of studies collect high-throughput, sub-second level raw acceleration data. In this paper, we discuss problems related to the collection and analysis of raw accelerometry data and refer to published solutions. In particular, we describe the size and complexity of the data, the within- and between-subject variability, and the effects of sensor location on the body. We also discuss challenges related to sampling frequency, device calibration, data labeling and multiple PA monitors synchronization. We illustrate these points using the Developmental Epidemiological Cohort Study (DECOS), which collected raw accelerometry data on individuals both in a controlled and the free-living environment.
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http://dx.doi.org/10.1007/s12561-018-9227-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874221PMC
July 2019

Multi-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration.

Nat Commun 2019 11 12;10(1):5121. Epub 2019 Nov 12.

Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, Netherlands.

Both short and long sleep are associated with an adverse lipid profile, likely through different biological pathways. To elucidate the biology of sleep-associated adverse lipid profile, we conduct multi-ancestry genome-wide sleep-SNP interaction analyses on three lipid traits (HDL-c, LDL-c and triglycerides). In the total study sample (discovery + replication) of 126,926 individuals from 5 different ancestry groups, when considering either long or short total sleep time interactions in joint analyses, we identify 49 previously unreported lipid loci, and 10 additional previously unreported lipid loci in a restricted sample of European-ancestry cohorts. In addition, we identify new gene-sleep interactions for known lipid loci such as LPL and PCSK9. The previously unreported lipid loci have a modest explained variance in lipid levels: most notable, gene-short-sleep interactions explain 4.25% of the variance in triglyceride level. Collectively, these findings contribute to our understanding of the biological mechanisms involved in sleep-associated adverse lipid profiles.
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http://dx.doi.org/10.1038/s41467-019-12958-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851116PMC
November 2019

Associations of autozygosity with a broad range of human phenotypes.

Nat Commun 2019 10 31;10(1):4957. Epub 2019 Oct 31.

Department of Neurology, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht University, Utrecht, 3584 CX, The Netherlands.

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F) for >1.4 million individuals, we show that F is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F are confirmed within full-sibling pairs, where the variation in F is independent of all environmental confounding.
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http://dx.doi.org/10.1038/s41467-019-12283-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823371PMC
October 2019

HDAC9 is implicated in atherosclerotic aortic calcification and affects vascular smooth muscle cell phenotype.

Nat Genet 2019 11 28;51(11):1580-1587. Epub 2019 Oct 28.

National Heart, Lung, and Blood Institute Framingham Heart Study, Framingham, MA, USA.

Aortic calcification is an important independent predictor of future cardiovascular events. We performed a genome-wide association meta-analysis to determine SNPs associated with the extent of abdominal aortic calcification (n = 9,417) or descending thoracic aortic calcification (n = 8,422). Two genetic loci, HDAC9 and RAP1GAP, were associated with abdominal aortic calcification at a genome-wide level (P < 5.0 × 10). No SNPs were associated with thoracic aortic calcification at the genome-wide threshold. Increased expression of HDAC9 in human aortic smooth muscle cells promoted calcification and reduced contractility, while inhibition of HDAC9 in human aortic smooth muscle cells inhibited calcification and enhanced cell contractility. In matrix Gla protein-deficient mice, a model of human vascular calcification, mice lacking HDAC9 had a 40% reduction in aortic calcification and improved survival. This translational genomic study identifies the first genetic risk locus associated with calcification of the abdominal aorta and describes a previously unknown role for HDAC9 in the development of vascular calcification.
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http://dx.doi.org/10.1038/s41588-019-0514-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858575PMC
November 2019
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