Publications by authors named "Ryan L Minster"

43 Publications

A murine model of the human CREBRFR457Q obesity-risk variant does not influence energy or glucose homeostasis in response to nutritional stress.

PLoS One 2021 14;16(9):e0251895. Epub 2021 Sep 14.

Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, United States of America.

Obesity and diabetes have strong heritable components, yet the genetic contributions to these diseases remain largely unexplained. In humans, a missense variant in Creb3 regulatory factor (CREBRF) [rs373863828 (p.Arg457Gln); CREBRFR457Q] is strongly associated with increased odds of obesity but decreased odds of diabetes. Although virtually nothing is known about CREBRF's mechanism of action, emerging evidence implicates it in the adaptive transcriptional response to nutritional stress downstream of TORC1. The objectives of this study were to generate a murine model with knockin of the orthologous variant in mice (CREBRFR458Q) and to test the hypothesis that this CREBRF variant promotes obesity and protects against diabetes by regulating energy and glucose homeostasis downstream of TORC1. To test this hypothesis, we performed extensive phenotypic analysis of CREBRFR458Q knockin mice at baseline and in response to acute (fasting/refeeding), chronic (low- and high-fat diet feeding), and extreme (prolonged fasting) nutritional stress as well as with pharmacological TORC1 inhibition, and aging to 52 weeks. The results demonstrate that the murine CREBRFR458Q model of the human CREBRFR457Q variant does not influence energy/glucose homeostasis in response to these interventions, with the exception of possible greater loss of fat relative to lean mass with age. Alternative preclinical models and/or studies in humans will be required to decipher the mechanisms linking this variant to human health and disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0251895PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8439463PMC
September 2021

Pleiotropic effects between cardiovascular disease risk factors and measures of cognitive and physical function in long-lived adults.

Sci Rep 2021 Sep 9;11(1):17980. Epub 2021 Sep 9.

Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA, USA.

Cardiovacular disease (CVD) is the leading cause of death among older adults and is often accompanied by functional decline. It is unclear what is driving this co-occurrence, but it may be behavioral, environmental and/or genetic. We used a family-based study to estimate the phenotypic and shared genetic correlation between CVD risk factors and physical and cognitive functional measures. Participants (n = 1,881) were from the Long Life Family Study, which enrolled families based on their exceptional longevity (sample mean age = 69.4 years, 44% female). Cardiovascular disease risk factors included carotid vessel measures [intima-media thickness and inter-adventitial diameter], obesity [body mass index (BMI) and waist circumference], and hypertension [systolic and diastolic blood pressures]. Function was measured in the physical [gait speed, grip strength, chair stand] and cognitive [digital symbol substitution test, retained and working memory, semantic fluency, and trail making tests] domains. We used SOLAR to estimate the genetic, environmental, and phenotypic correlation between each pair adjusting for age, age, sex, field center, smoking, height, and weight. There were significant phenotypic correlations (range |0.05-0.22|) between CVD risk factors and physical and cognitive function (all P < 0.05). Most significant genetic correlations (range |0.21-0.62|) were between CVD risk factorsand cognitive function, although BMI and waist circumference had significant genetic correlation with gait speed and chair stand time (range |0.29-0.53|; all P < 0.05). These results suggest that CVD risk factors may share a common genetic-and thus, biologic-basis with both cognitive and physical function. This is particularly informative for research into the genetic determinants of chronic disease.
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http://dx.doi.org/10.1038/s41598-021-97298-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8429644PMC
September 2021

The impact of global and local Polynesian genetic ancestry on complex traits in Native Hawaiians.

PLoS Genet 2021 02 11;17(2):e1009273. Epub 2021 Feb 11.

Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.

Epidemiological studies of obesity, Type-2 diabetes (T2D), cardiovascular diseases and several common cancers have revealed an increased risk in Native Hawaiians compared to European- or Asian-Americans living in the Hawaiian islands. However, there remains a gap in our understanding of the genetic factors that affect the health of Native Hawaiians. To fill this gap, we studied the genetic risk factors at both the chromosomal and sub-chromosomal scales using genome-wide SNP array data on ~4,000 Native Hawaiians from the Multiethnic Cohort. We estimated the genomic proportion of Native Hawaiian ancestry ("global ancestry," which we presumed to be Polynesian in origin), as well as this ancestral component along each chromosome ("local ancestry") and tested their respective association with binary and quantitative cardiometabolic traits. After attempting to adjust for non-genetic covariates evaluated through questionnaires, we found that per 10% increase in global Polynesian genetic ancestry, there is a respective 8.6%, and 11.0% increase in the odds of being diabetic (P = 1.65×10-4) and having heart failure (P = 2.18×10-4), as well as a 0.059 s.d. increase in BMI (P = 1.04×10-10). When testing the association of local Polynesian ancestry with risk of disease or biomarkers, we identified a chr6 region associated with T2D. This association was driven by an uniquely prevalent variant in Polynesian ancestry individuals. However, we could not replicate this finding in an independent Polynesian cohort from Samoa due to the small sample size of the replication cohort. In conclusion, we showed that Polynesian ancestry, which likely capture both genetic and lifestyle risk factors, is associated with an increased risk of obesity, Type-2 diabetes, and heart failure, and that larger cohorts of Polynesian ancestry individuals will be needed to replicate the putative association on chr6 with T2D.
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http://dx.doi.org/10.1371/journal.pgen.1009273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877570PMC
February 2021

Relationship Between Serum IGF-1 and BMI Differs by Age.

J Gerontol A Biol Sci Med Sci 2021 Jun;76(7):1303-1308

Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pennsylvania.

Background: 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.
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http://dx.doi.org/10.1093/gerona/glaa282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202150PMC
June 2021

ECHS1 disease in two unrelated families of Samoan descent: Common variant - rare disorder.

Am J Med Genet A 2021 01 28;185(1):157-167. Epub 2020 Oct 28.

Division of Metabolic Disorders, CHOC Children's Hospital, Orange, California, USA.

Mutations in the short-chain enoyl-CoA hydratase (SCEH) gene, ECHS1, cause a rare autosomal recessive disorder of valine catabolism. Patients usually present with developmental delay, regression, dystonia, feeding difficulties, and abnormal MRI with bilateral basal ganglia involvement. We present clinical, biochemical, molecular, and functional data for four affected patients from two unrelated families of Samoan descent with identical novel compound heterozygous mutations. Family 1 has three affected boys while Family 2 has an affected daughter, all with clinical and MRI findings of Leigh syndrome and intermittent episodes of acidosis and ketosis. WES identified a single heterozygous variant in ECHS1 at position c.832G > A (p.Ala278Thr). However, western blot revealed significantly reduced ECHS1 protein for all affected family members. Decreased SCEH activity in fibroblasts and a mild increase in marker metabolites in urine further supported ECHS1 as the underlying gene defect. Additional investigations at the DNA (aCGH, WGS) and RNA (qPCR, RT-PCR, RNA-Seq, RNA-Array) level identified a silent, common variant at position c.489G > A (p.Pro163=) as the second mutation. This substitution, present at high frequency in the Samoan population, is associated with decreased levels of normally spliced mRNA. To our understanding, this is the first report of a novel, hypomorphic allele c.489G > A (p.Pro163=), associated with SCEH deficiency.
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http://dx.doi.org/10.1002/ajmg.a.61936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746601PMC
January 2021

Genome-wide association studies in Samoans give insight into the genetic architecture of fasting serum lipid levels.

J Hum Genet 2021 Feb 5;66(2):111-121. Epub 2020 Aug 5.

Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.

The current understanding of the genetic architecture of lipids has largely come from genome-wide association studies (GWAS). To date, few GWAS have examined the genetic architecture of lipids in Polynesians, and none have in Samoans, whose unique population history, including many population bottlenecks, may provide insight into the biological foundations of variation in lipid levels. Here we performed a GWAS of four fasting serum lipid levels: total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides (TG) in a sample of 2849 Samoans, with validation genotyping for associations in a replication cohort comprising 1798 Samoans and American Samoans. We identified multiple genome-wide significant associations (P < 5 × 10) previously seen in other populations-APOA1 with TG, CETP with HDL, and APOE with TC and LDL-and several suggestive associations (P < 1 × 10), including an association of variants downstream of MGAT1 and RAB21 with HDL. However, we observed different association signals for variants near APOE than what has been previously reported in non-Polynesian populations. The association with several known lipid loci combined with the newly identified associations with variants near MGAT1 and RAB21 suggest that while some of the genetic architecture of lipids is shared between Samoans and other populations, part of the genetic architecture may be Polynesian-specific.
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http://dx.doi.org/10.1038/s10038-020-0816-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785639PMC
February 2021

Exploring the Paradoxical Relationship of a Creb 3 Regulatory Factor Missense Variant With Body Mass Index and Diabetes Among Samoans: Protocol for the Soifua Manuia (Good Health) Observational Cohort Study.

JMIR Res Protoc 2020 Jul 23;9(7):e17329. Epub 2020 Jul 23.

Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States.

Background: The prevalence of obesity and diabetes in Samoa, like many other Pacific Island nations, has reached epidemic proportions. Although the etiology of these conditions can be largely attributed to the rapidly changing economic and nutritional environment, a recently identified genetic variant, rs373863828 (CREB 3 regulatory factor, CREBRF: c.1370G>A p.[R457Q]) is associated with increased odds of obesity, but paradoxically, decreased odds of diabetes.

Objective: The overarching goal of the Soifua Manuia (Good Health) study was to precisely characterize the association of the CREBRF variant with metabolic (body composition and glucose homeostasis) and behavioral traits (dietary intake, physical activity, sleep, and weight control behaviors) that influence energy homeostasis in 500 adults.

Methods: A cohort of adult Samoans who participated in a genome-wide association study of adiposity in Samoa in 2010 was followed up, based on the presence or absence of the CREBRF variant, between August 2017 and March 2019. Over a period of 7-10 days, each participant completed the main study protocol, which consisted of anthropometric measurements (weight, height, circumferences, and skinfolds), body composition assessment (bioelectrical impedance and dual-energy x-ray absorptiometry), point-of-care glycated hemoglobin measurement, a fasting blood draw and oral glucose tolerance test, urine collection, blood pressure measurement, hand grip strength measurement, objective physical activity and sleep apnea monitoring, and questionnaire measures (eg, health interview, cigarette and alcohol use, food frequency questionnaire, socioeconomic position, stress, social support, food and water insecurity, sleep, body image, and dietary preferences). In January 2019, a subsample of the study participants (n=118) completed a buttock fat biopsy procedure to collect subcutaneous adipose tissue samples.

Results: Enrollment of 519 participants was completed in March 2019. Data analyses are ongoing, with results expected in 2020 and 2021.

Conclusions: While the genetic variant rs373863828, in CREBRF, has the largest known effect size of any identified common obesity gene, very little is currently understood about the mechanisms by which it confers increased odds of obesity but paradoxically lowered odds of type 2 diabetes. The results of this study will provide insights into how the gene functions on a whole-body level, which could provide novel targets to prevent or treat obesity, diabetes, and associated metabolic disorders. This study represents the human arm of a comprehensive and integrated approach involving humans as well as preclinical models that will provide novel insights into metabolic disease.

International Registered Report Identifier (irrid): RR1-10.2196/17329.
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http://dx.doi.org/10.2196/17329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413272PMC
July 2020

Evolutionary history of modern Samoans.

Proc Natl Acad Sci U S A 2020 04 14;117(17):9458-9465. Epub 2020 Apr 14.

Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD 21201;

Archaeological studies estimate the initial settlement of Samoa at 2,750 to 2,880 y ago and identify only limited settlement and human modification to the landscape until about 1,000 to 1,500 y ago. At this point, a complex history of migration is thought to have begun with the arrival of people sharing ancestry with Near Oceanic groups (i.e., Austronesian-speaking and Papuan-speaking groups), and was then followed by the arrival of non-Oceanic groups during European colonialism. However, the specifics of this peopling are not entirely clear from the archaeological and anthropological records, and is therefore a focus of continued debate. To shed additional light on the Samoan population history that this peopling reflects, we employ a population genetic approach to analyze 1,197 Samoan high-coverage whole genomes. We identify population splits between the major Samoan islands and detect asymmetrical gene flow to the capital city. We also find an extreme bottleneck until about 1,000 y ago, which is followed by distinct expansions across the islands and subsequent bottlenecks consistent with European colonization. These results provide for an increased understanding of Samoan population history and the dynamics that inform it, and also demonstrate how rapid demographic processes can shape modern genomes.
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http://dx.doi.org/10.1073/pnas.1913157117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196816PMC
April 2020

Genetic Variability in the Iron Homeostasis Pathway and Patient Outcomes After Aneurysmal Subarachnoid Hemorrhage.

Neurocrit Care 2020 12;33(3):749-758

Department of Health Promotion and Development, School of Nursing, University of Pittsburgh, 440 Victoria Building, 3500 Victoria Street, Pittsburgh, PA, 15261, USA.

Background/objective: Iron can be detrimental to most tissues both in excess and in deficiency. The brain in particular is highly susceptible to the consequences of excessive iron, especially during blood brain barrier disruption after injury. Preliminary evidence suggests that iron homeostasis is important during recovery after neurologic injury; therefore, the exploration of genetic variability in genes involved in iron homeostasis is an important area of patient outcomes research. The purpose of this study was to examine the relationship between tagging single nucleotide polymorphisms (SNPs) in candidate genes related to iron homeostasis and acute and long-term patient outcomes after aneurysmal subarachnoid hemorrhage (aSAH).

Methods: This study was a longitudinal, observational, candidate gene association study of participants with aSAH that used a two-tier design including tier 1 (discovery, n = 197) and tier 2 (replication, n = 277). Participants were followed during the acute outcome phase for development of cerebral vasospasm and delayed cerebral ischemia (DCI) and during the long-term outcome phase for death and gross functional outcome using the Glasgow Outcome Scale (GOS; poor = 1-3). Genetic association analyses were performed using a logistic regression model adjusted for age, sex, and Fisher grade. Approximate Bayes factors (ABF) and Bayesian false discovery probabilities (BFDP) were used to prioritize and interpret results.

Results: In tier 1, 235 tagging SNPs in 28 candidate genes were available for analysis and 26 associations (20 unique SNPs in 12 genes) were nominated for replication in tier 2. In tier 2, we observed an increase in evidence of association for three associations in the ceruloplasmin (CP) and cubilin (CUBN) genes. We observed an association of rs17838831 (CP) with GOS at 3 months (tier 2 results, odds ratio [OR] = 2.10, 95% confidence interval [CI] = 1.14-3.86, p = 0.018, ABF = 0.52, and BFDP = 70.8%) and GOS at 12 months (tier 2 results, OR = 1.86, 95% CI 0.98-3.52, p = 0.058, ABF = 0.72, and BFDP = 77.3%) as well as rs10904850 (CUBN) with DCI (tier 2 results, OR = 0.70, 95% CI 0.48-1.02, p = 0.064, ABF = 0.59, and BFDP = 71.8%).

Conclusions: Among the genes examined, our findings support a role for CP and CUBN in patient outcomes after aSAH. In an effort to translate these findings into clinical utility and improve outcomes after aSAH, additional research is needed to examine the functional roles of these genes after aSAH.
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http://dx.doi.org/10.1007/s12028-020-00961-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541432PMC
December 2020

A missense variant in CREBRF is associated with taller stature in Samoans.

Am J Hum Biol 2020 11 19;32(6):e23414. Epub 2020 Mar 19.

Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Objectives: Studies have demonstrated that rs373863828, a missense variant in CREBRF, is associated with a number of anthropometric traits including body mass index (BMI), obesity, percent body fat, hip circumference, and abdominal circumference. Given the biological relationship between height and adiposity, we hypothesized that the effect of this variant on BMI might be due in part to an association of this variant with height.

Methods: We tested the hypothesis that minor allele of rs373863828 is associated with height in a Samoan population in two adult cohorts and in a separate cohort of children (age 5-18 years old) using linear mixed modeling.

Results: We found evidence of a strong relationship between rs373863828 and greater mean height in Samoan adults (0.77 cm greater average height for each copy of the minor allele) with the same direction of effect in Samoan children.

Conclusions: These results suggest that the missense variant rs373863828 in CREBRF, first identified through an association with larger BMI, may be related to an underlying biological mechanism affecting overall body size including stature.
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http://dx.doi.org/10.1002/ajhb.23414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501196PMC
November 2020

Genome-wide linkage analysis of carotid artery traits in exceptionally long-lived families.

Atherosclerosis 2019 12 10;291:19-26. Epub 2019 Oct 10.

Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA, USA; Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA.

Background And Aims: Atherosclerosis develops with age and is partially controlled by genetics. Research to date has identified common variants with small effects on atherosclerosis related traits. We aimed to use family-based genome-wide linkage analysis to identify chromosomal regions potentially harboring rare variants with larger effects for atherosclerosis related traits.

Methods: Participants included 2205 individuals from the Long Life Family Study (LLFS), which recruited families with exceptional longevity from Boston, New York, Pittsburgh, and Denmark. Participants underwent B-mode ultrasonography of the carotid arteries to measure intima-media thickness (IMT), inter-adventitial diameter (IAD), and plaque presence and severity. We conducted residual heritability and genome-wide linkage analyses adjusted for age, age, sex, and field center using pedigree-based maximum-likelihood methods in SOLAR.

Results: All carotid traits were significantly heritable with a range of 0.68 for IAD to 0.38 for IMT. We identified three chromosomal regions with linkage to IAD (3q13; max LOD 5.3), plaque severity (17q22-q23, max LOD 3.2), and plaque presence (17q24, max LOD 3.1). No common allelic variants within these linkage peaks were associated with the carotid artery traits.

Conclusions: We identified three chromosomal regions with evidence of linkage to carotid artery diameter and atherosclerotic plaque in exceptionally long-lived families. Since common allelic variants within our linkage peaks did not account for our findings, future follow-up resequencing of these regions in LLFS families should help advance our understanding of atherosclerosis, CVD, and healthy vascular aging.
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http://dx.doi.org/10.1016/j.atherosclerosis.2019.10.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899182PMC
December 2019

Heterogeneity of healthy aging: comparing long-lived families across five healthy aging phenotypes of blood pressure, memory, pulmonary function, grip strength, and metabolism.

Geroscience 2019 08 22;41(4):383-393. Epub 2019 Jul 22.

Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, 5126 Public Health, 130 DeSoto Street, Pittsburgh, PA, 15261, USA.

Five healthy aging phenotypes were developed in the Long Life Family Study to uncover longevity pathways and determine if healthy aging across multiple systems clustered in a subset of long-lived families. Using blood pressure, memory, pulmonary function, grip strength, and metabolic measures (body mass index, waist circumference and fasting levels of glucose, insulin, triglycerides, lipids, and inflammatory markers), offspring were ranked according to relative health using gender-, age-, and relevant confounder-adjusted z-scores. Based on our prior work, families met a healthy aging phenotype if ≥ 2 and ≥ 50% of their offspring were exceptionally healthy for that respective phenotype. Among 426 families, only two families met criteria for three healthy aging phenotypes and none met criteria for four or more healthy aging phenotypes. Using Spearman correlation, the proportion of offspring within families with exceptionally healthy pulmonary function was correlated with the proportion of offspring within families with exceptional strength (r = 0.19, p = 0.002). The proportion of offspring within families meeting the healthy blood pressure and metabolic phenotypes were also correlated (r = 0.14, p = 0.006), and more families were classified as meeting healthy blood pressure and metabolic phenotypes (Kappa = 0.10, p = 0.02), as well as the healthy pulmonary and blood pressure phenotypes than expected by chance (Kappa = 0.09, p = 0.03). Other phenotypes were weakly correlated (|r| ≤ 0.07) with low pairwise agreement (Kappa ≤ 0.06). Among these families selected for familial longevity, correspondence between healthy aging phenotypes was weak, supporting the heterogeneous nature of longevity and suggesting biological underpinnings of each individual phenotype should be examined separately to determine their shared and unique determinants.
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http://dx.doi.org/10.1007/s11357-019-00086-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815318PMC
August 2019

Discordant association of the CREBRF rs373863828 A allele with increased BMI and protection from type 2 diabetes in Māori and Pacific (Polynesian) people living in Aotearoa/New Zealand.

Diabetologia 2018 07 2;61(7):1603-1613. Epub 2018 May 2.

Department of Biochemistry, University of Otago, 710 Cumberland Street, Dunedin, 9054, New Zealand.

Aims/hypothesis: The A (minor) allele of CREBRF rs373863828 has been associated with increased BMI and reduced risk of type 2 diabetes in the Samoan populations of Samoa and American Samoa. Our aim was to test rs373863828 for associations with BMI and the odds of type 2 diabetes, gout and chronic kidney disease (CKD) in Māori and Pacific (Polynesian) people living in Aotearoa/New Zealand.

Methods: Linear and logistic regression models were used to analyse the association of the A allele of CREBRF rs373863828 with BMI, log-transformed BMI, waist circumference, type 2 diabetes, gout and CKD in 2286 adults. The primary analyses were adjusted for age, sex, the first four genome-wide principal components and (where appropriate) BMI, waist circumference and type 2 diabetes. The primary analysis was conducted in ancestrally defined groups and association effects were combined using meta-analysis.

Results: For the A allele of rs373863828, the effect size was 0.038 (95% CI 0.022, 0.055, p = 4.8 × 10) for log-transformed BMI, with OR 0.59 (95% CI 0.47, 0.73, p = 1.9 × 10) for type 2 diabetes. There was no evidence for an association of genotype with variance in BMI (p = 0.13), and nor was there evidence for associations with serum urate (β = 0.012 mmol/l, p = 0.10), gout (OR 1.00, p = 0.98) or CKD (OR 0.91, p = 0.59).

Conclusions/interpretation: Our results in New Zealand Polynesian adults replicate, with very similar effect sizes, the association of the A allele of rs373863828 with higher BMI but lower odds of type 2 diabetes among Samoan adults living in Samoa and American Samoa.
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http://dx.doi.org/10.1007/s00125-018-4623-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6434933PMC
July 2018

A novel healthy blood pressure phenotype in the Long Life Family Study.

J Hypertens 2018 01;36(1):43-53

Department of Epidemiology.

Background: Hypertension tends to run in families and has both genetic and environmental determinants. We assessed the hypothesis that a novel healthy blood pressure (BP) phenotype is also familial and sought to identify its associated factors.

Methods: We developed a healthy BP phenotype in the Long Life Family Study, a cohort of two-generation families selected for longevity. Participants from the offspring generation (n = 2211, ages 32-88) were classified as having healthy BP if their age-adjusted and sex-adjusted SBP z-score was between -1.5 and -0.5. Offspring on antihypertensive medications were classified as not having healthy BP. Families with at least two offspring (n = 419 families) were defined as meeting the healthy BP phenotype if at least two and at least 50% of their offspring had healthy BP.

Results: Among 2211 offspring, 476 (21.5%) met the healthy BP phenotype. When examining the 419 families, only 44 (10.5%) families met the criteria for the healthy BP phenotype. Both offspring and probands from families with healthy BP performed better on neuropsychological tests that place demands on complex attention and executive function when compared with offspring and probands from remaining families. Among families with the healthy BP phenotype compared with families without, a higher proportion of offspring met the American Heart Association definition of ideal cardiovascular health (10.8 versus 3.8%, respectively; driven by BP, smoking status, and BMI components).

Conclusion: In this cohort of familial longevity, few families had a novel healthy BP phenotype in multiple members. Families with this healthy BP phenotype may represent a specific pathway to familial longevity.
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http://dx.doi.org/10.1097/HJH.0000000000001514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5893936PMC
January 2018

Energy Expenditure in Vinyasa Yoga Versus Walking.

J Phys Act Health 2017 08 19;14(8):597-605. Epub 2017 Apr 19.

Background: Whether the energy cost of vinyasa yoga meets the criteria for moderate-to-vigorous physical activity has not been established.

Purpose: To compare energy expenditure during acute bouts of vinyasa yoga and 2 walking protocols.

Methods: Participants (20 males, 18 females) performed 60-minute sessions of vinyasa yoga (YOGA), treadmill walking at a self-selected brisk pace (SELF), and treadmill walking at a pace that matched the heart rate of the YOGA session (HR-Match). Energy expenditure was assessed via indirect calorimetry.

Results: Energy expenditure was significantly lower in YOGA compared with HR-Match (difference = 79.5 ± 44.3 kcal; P < .001) and SELF (difference = 51.7 ± 62.6 kcal; P < .001), but not in SELF compared with HR-Match (difference = 27.8 ± 72.6 kcal; P = .054). A similar pattern was observed for metabolic equivalents (HR-Match = 4.7 ± 0.8, SELF = 4.4 ± 0.7, YOGA = 3.6 ± 0.6; P < .001). Analyses using only the initial 45 minutes from each of the sessions, which excluded the restorative component of YOGA, showed energy expenditure was significantly lower in YOGA compared with HR-Match (difference = 68.0 ± 40.1 kcal; P < .001) but not compared with SELF (difference = 15.1 ± 48.7 kcal; P = .189).

Conclusions: YOGA meets the criteria for moderate-intensity physical activity. Thus, YOGA may be a viable form of physical activity to achieve public health guidelines and to elicit health benefits.
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http://dx.doi.org/10.1123/jpah.2016-0548DOI Listing
August 2017

Genomewide Association Scan of a Mortality Associated Endophenotype for a Long and Healthy Life in the Long Life Family Study.

J Gerontol A Biol Sci Med Sci 2017 Oct;72(10):1411-1416

Department of Human Genetics, University of Pittsburgh, Pennsylvania.

Background: Identification of genes or fundamental biological pathways that regulate aging phenotypes and longevity could lead to possible interventions to increase healthy longevity.

Methods: Using data from the Long Life Family Study, we performed genomewide association analyses on an endophenotype construct, LF1, comprising a linear combination of traits across health domains. LF1 primarily reflected traits from the pulmonary and physical activity domains.

Results: We detected a significant association between LF1 and a locus on chromosome 10p15 (p-value = 4.65 × 10-8) and suggestive evidence (p-value < 5 × 10-6) for association on chromosomes 1, 2, 8, 12, 15, 18, and 22. Using data from the Health, Aging and Body Composition Study, we subsequently replicated the association for the 1p13 region near the NBPF6 locus (p-value = 3.65 × 10-4).

Conclusions: Our analyses indicate that loci influencing a healthy aging endophenotype construct predominantly comprised of pulmonary and physical function domains may be located on chromosome 1p13 near the NBPF6 locus. Further investigation of this possible locus and other suggestive loci may reveal novel biological pathways that influence healthy aging.
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http://dx.doi.org/10.1093/gerona/glx011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5861859PMC
October 2017

A thrifty variant in CREBRF strongly influences body mass index in Samoans.

Nat Genet 2016 09 25;48(9):1049-1054. Epub 2016 Jul 25.

International Health Institute, Department of Epidemiology, Brown University School of Public Health, Providence, Rhode Island, USA.

Samoans are a unique founder population with a high prevalence of obesity, making them well suited for identifying new genetic contributors to obesity. We conducted a genome-wide association study (GWAS) in 3,072 Samoans, discovered a variant, rs12513649, strongly associated with body mass index (BMI) (P = 5.3 × 10(-14)), and replicated the association in 2,102 additional Samoans (P = 1.2 × 10(-9)). Targeted sequencing identified a strongly associated missense variant, rs373863828 (p.Arg457Gln), in CREBRF (meta P = 1.4 × 10(-20)). Although this variant is extremely rare in other populations, it is common in Samoans (frequency of 0.259), with an effect size much larger than that of any other known common BMI risk variant (1.36-1.45 kg/m(2) per copy of the risk-associated allele). In comparison to wild-type CREBRF, the Arg457Gln variant when overexpressed selectively decreased energy use and increased fat storage in an adipocyte cell model. These data, in combination with evidence of positive selection of the allele encoding p.Arg457Gln, support a 'thrifty' variant hypothesis as a factor in human obesity.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5069069PMC
http://dx.doi.org/10.1038/ng.3620DOI Listing
September 2016

Association Between Mortality and Heritability of the Scale of Aging Vigor in Epidemiology.

J Am Geriatr Soc 2016 08 13;64(8):1679-83. Epub 2016 Jun 13.

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

Objectives: To investigate the association between mortality and heritability of a rescaled Fried frailty index, the Scale of Aging Vigor in Epidemiology (SAVE), to determine its value for genetic analyses.

Design: Longitudinal, community-based cohort study.

Setting: The Long Life Family Study (LLFS) in the United States and Denmark.

Participants: Long-lived individuals (N = 4,875, including 4,075 genetically related individuals) and their families (N = 551).

Measurements: The SAVE was administered to 3,599 participants and included weight change, weakness (grip strength), fatigue (questionnaire), physical activity (days walked in prior 2 weeks), and slowness (gait speed); each component was scored 0, 1, or 2 using approximate tertiles, and summed (range 0 (vigorous) to 10 (frail)). Heritability was determined using a variance component-based family analysis using a polygenic model. Association with mortality in the proband generation (N = 1,421) was calculated using Cox proportional hazards mixed-effect models.

Results: Heritability of the SAVE was 0.23 (P < .001) overall (n = 3,599), 0.31 (P < .001) in probands (n = 1,479), and 0.26 (P < .001) in offspring (n = 2,120). In adjusted models, higher SAVE scores were associated with higher mortality (score 5-6: hazard ratio (HR) = 2.83, 95% confidence interval (CI) = 1.46-5.51; score 7-10: HR = 3.40, 95% CI = 1.72-6.71) than lower scores (0-2).

Conclusion: The SAVE was associated with mortality and was moderately heritable in the LLFS, suggesting a genetic component to age-related vigor and frailty and supporting its use for further genetic analyses.
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http://dx.doi.org/10.1111/jgs.14190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4988884PMC
August 2016

Genome-Wide Association Study and Linkage Analysis of the Healthy Aging Index.

J Gerontol A Biol Sci Med Sci 2015 Aug 10;70(8):1003-8. Epub 2015 Mar 10.

Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pennsylvania.

Background: The Healthy Aging Index (HAI) is a tool for measuring the extent of health and disease across multiple systems.

Methods: We conducted a genome-wide association study and a genome-wide linkage analysis to map quantitative trait loci associated with the HAI and a modified HAI weighted for mortality risk in 3,140 individuals selected for familial longevity from the Long Life Family Study. The genome-wide association study used the Long Life Family Study as the discovery cohort and individuals from the Cardiovascular Health Study and the Framingham Heart Study as replication cohorts.

Results: There were no genome-wide significant findings from the genome-wide association study; however, several single-nucleotide polymorphisms near ZNF704 on chromosome 8q21.13 were suggestively associated with the HAI in the Long Life Family Study (p < 10(-) (6)) and nominally replicated in the Cardiovascular Health Study and Framingham Heart Study. Linkage results revealed significant evidence (log-odds score = 3.36) for a quantitative trait locus for mortality-optimized HAI in women on chromosome 9p24-p23. However, results of fine-mapping studies did not implicate any specific candidate genes within this region of interest.

Conclusions: ZNF704 may be a potential candidate gene for studies of the genetic underpinnings of longevity.
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http://dx.doi.org/10.1093/gerona/glv006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4506316PMC
August 2015

Genetic variants associated with lung function: the long life family study.

Respir Res 2014 Nov 1;15:134. Epub 2014 Nov 1.

Department of Laboratory Medicine and Pathology, University of Minnesota, 515 Delaware Street SE, 1-136 Moos Towers, Minneapolis 55455, MN, USA.

Background: Reduced forced expiratory volume in 1 second (FEV1) and the ratio of FEV1 to forced vital capacity (FVC) are strong predictors of mortality and lung function is higher among individuals with exceptional longevity. However, genetic factors associated with lung function in individuals with exceptional longevity have not been identified.

Method: We conducted a genome wide association study (GWAS) to identify novel genetic variants associated with lung function in the Long Life Family Study (LLFS) (n = 3,899). Replication was performed using data from the CHARGE/SpiroMeta consortia. The association between SNPs and FEV1 and FEV1/FVC was analyzed using a linear mixed effects model adjusted for age, age2, sex, height, field center, ancestry principal components and kinship structure to adjust for family relationships separately for ever smokers and never smokers. In the linkage analysis, we used the residuals of the FEV1 and FEV1/FVC, adjusted for age, sex, height, ancestry principal components (PCs), smoking status, pack-years, and field center.

Results: We identified nine SNPs in strong linkage disequilibrium in the CYP2U1 gene to be associated with FEV1 and a novel SNP (rs889574) associated with FEV1/FVC, none of which were replicated in the CHARGE/SpiroMeta consortia. Using linkage analysis, we identified a novel linkage peak in chromosome 2 at 219 cM for FEV1/FVC (LOD: 3.29) and confirmed a previously reported linkage peak in chromosome 6 at 28 cM (LOD: 3.33) for FEV1.

Conclusion: Future studies need to identify the rare genetic variants underlying the linkage peak in chromosome 6 for FEV1.
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http://dx.doi.org/10.1186/s12931-014-0134-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4228089PMC
November 2014

Stratified randomization controls better for batch effects in 450K methylation analysis: a cautionary tale.

Front Genet 2014 13;5:354. Epub 2014 Oct 13.

Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh Pittsburgh, PA, USA ; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh Pittsburgh, PA, USA.

Background: Batch effects in DNA methylation microarray experiments can lead to spurious results if not properly handled during the plating of samples.

Methods: Two pilot studies examining the association of DNA methylation patterns across the genome with obesity in Samoan men were investigated for chip- and row-specific batch effects. For each study, the DNA of 46 obese men and 46 lean men were assayed using Illumina's Infinium HumanMethylation450 BeadChip. In the first study (Sample One), samples from obese and lean subjects were examined on separate chips. In the second study (Sample Two), the samples were balanced on the chips by lean/obese status, age group, and census region. We used methylumi, watermelon, and limma R packages, as well as ComBat, to analyze the data. Principal component analysis and linear regression were, respectively, employed to identify the top principal components and to test for their association with the batches and lean/obese status. To identify differentially methylated positions (DMPs) between obese and lean males at each locus, we used a moderated t-test.

Results: Chip effects were effectively removed from Sample Two but not Sample One. In addition, dramatic differences were observed between the two sets of DMP results. After "removing" batch effects with ComBat, Sample One had 94,191 probes differentially methylated at a q-value threshold of 0.05 while Sample Two had zero differentially methylated probes. The disparate results from Sample One and Sample Two likely arise due to the confounding of lean/obese status with chip and row batch effects.

Conclusion: Even the best possible statistical adjustments for batch effects may not completely remove them. Proper study design is vital for guarding against spurious findings due to such effects.
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http://dx.doi.org/10.3389/fgene.2014.00354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4195366PMC
October 2014

Genome-wide association analysis identifies six new loci associated with forced vital capacity.

Nat Genet 2014 Jul 15;46(7):669-77. Epub 2014 Jun 15.

Centre for Population Health Sciences, Medical School, University of Edinburgh, Edinburgh, UK.

Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10(-8)) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.
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http://dx.doi.org/10.1038/ng.3011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4140093PMC
July 2014

Biomechanical properties of the skin in cutis laxa.

J Invest Dermatol 2014 Nov 20;134(11):2836-2838. Epub 2014 May 20.

Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, USA. Electronic address:

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http://dx.doi.org/10.1038/jid.2014.224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199921PMC
November 2014

Prevalence of adiposity and associated cardiometabolic risk factors in the Samoan genome-wide association study.

Am J Hum Biol 2014 Jul-Aug;26(4):491-501. Epub 2014 May 5.

Weight Control and Diabetes Research Center, The Miriam Hospital, Providence, Rhode Island; The Alpert Medical School, Brown University, Providence, Rhode Island.

Objective: To describe the prevalence of obesity-related noncommunicable diseases (NCDs) and associated risk factors in a sample of Samoan adults studied in 2010 as part of a genome-wide assocation study (GWAS) for obesity related traits.

Methods: Anthropometric and biochemical data collected from n = 3,475 participants (n = 1,437 male; n = 2,038 female) aged 24.5 to <65 years were used to describe the prevalence of obesity, diabetes, hypertension, and dyslipidemia within the study sample. One way analysis of variance, χ(2) tests, and binary logistic regression were used to identify differences in disease and risk factor prevalence by 10-year age group, gender, or by census region of residence.

Results: Obesity was highly prevalent among the study sample; 64.6% of females and 41.2% of males were obese according to Polynesian cutoffs (BMI ≥ 32 kg/m(2) ). Females were less likely than males to have hypertension (31.7% vs. 36.7%) but equally likely to have diabetes (17.8% vs. 16.4%). With the exception of obesity and low HDL-cholesterol in females only, there were significant differences in the prevalence of all NCDs and associated risk factors by age group, with the oldest age group (55 to <65 years) most affected. In both sexes, residents of the Apia Urban Area were at significantly greater risk of obesity, diabetes, low HDL-cholesterol, and high triglycerides than residents of the more rural Savaii region.

Conclusions: The phenotypic characteristics of this sample provide evidence of a continuation of previously reported temporal trends toward obesity and its associated disorders. Attention must be paid to the critical NCD situation in Samoa.
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http://dx.doi.org/10.1002/ajhb.22553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4292846PMC
January 2015

Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium.

Hum Mol Genet 2014 Jun 14;23(11):3054-68. Epub 2014 Jan 14.

Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 × 10(-8)) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 × 10(-14)). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 × 10(-6) also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology.
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http://dx.doi.org/10.1093/hmg/ddt675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4038791PMC
June 2014

Heritability of and mortality prediction with a longevity phenotype: the healthy aging index.

J Gerontol A Biol Sci Med Sci 2014 Apr 2;69(4):479-85. Epub 2013 Aug 2.

Graduate School of Public Health, University of Pittsburgh, A527 Crabtree Hall, 130 DeSoto Street, Pittsburgh, PA 15261.

Background: Longevity-associated genes may modulate risk for age-related diseases and survival. The Healthy Aging Index (HAI) may be a subphenotype of longevity, which can be constructed in many studies for genetic analysis. We investigated the HAI's association with survival in the Cardiovascular Health Study and heritability in the Long Life Family Study.

Methods: The HAI includes systolic blood pressure, pulmonary vital capacity, creatinine, fasting glucose, and Modified Mini-Mental Status Examination score, each scored 0, 1, or 2 using approximate tertiles and summed from 0 (healthy) to 10 (unhealthy). In Cardiovascular Health Study, the association with mortality and accuracy predicting death were determined with Cox proportional hazards analysis and c-statistics, respectively. In Long Life Family Study, heritability was determined with a variance component-based family analysis using a polygenic model.

Results: Cardiovascular Health Study participants with unhealthier index scores (7-10) had 2.62-fold (95% confidence interval: 2.22, 3.10) greater mortality than participants with healthier scores (0-2). The HAI alone predicted death moderately well (c-statistic = 0.643, 95% confidence interval: 0.626, 0.661, p < .0001) and slightly worse than age alone (c-statistic = 0.700, 95% confidence interval: 0.684, 0.717, p < .0001; p < .0001 for comparison of c-statistics). Prediction increased significantly with adjustment for demographics, health behaviors, and clinical comorbidities (c-statistic = 0.780, 95% confidence interval: 0.765, 0.794, p < .0001). In Long Life Family Study, the heritability of the HAI was 0.295 (p < .0001) overall, 0.387 (p < .0001) in probands, and 0.238 (p = .0004) in offspring.

Conclusion: The HAI should be investigated further as a candidate phenotype for uncovering longevity-associated genes in humans.
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http://dx.doi.org/10.1093/gerona/glt117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3968826PMC
April 2014

Assessment of gene-by-sex interaction effect on bone mineral density.

J Bone Miner Res 2012 Oct;27(10):2051-64

Department of Biostatistics, Boston University School of Public Health, 801 Massachusetts Avenue CT3, Boston,MA 02118, USA.

Sexual dimorphism in various bone phenotypes, including bone mineral density (BMD), is widely observed; however, the extent to which genes explain these sex differences is unclear. To identify variants with different effects by sex, we examined gene-by-sex autosomal interactions genome-wide, and performed expression quantitative trait loci (eQTL) analysis and bioinformatics network analysis. We conducted an autosomal genome-wide meta-analysis of gene-by-sex interaction on lumbar spine (LS) and femoral neck (FN) BMD in 25,353 individuals from 8 cohorts. In a second stage, we followed up the 12 top single-nucleotide polymorphisms (SNPs; p < 1 × 10(-5) ) in an additional set of 24,763 individuals. Gene-by-sex interaction and sex-specific effects were examined in these 12 SNPs. We detected one novel genome-wide significant interaction associated with LS-BMD at the Chr3p26.1-p25.1 locus, near the GRM7 gene (male effect = 0.02 and p = 3.0 × 10(-5) ; female effect = -0.007 and p = 3.3 × 10(-2) ), and 11 suggestive loci associated with either FN- or LS-BMD in discovery cohorts. However, there was no evidence for genome-wide significant (p < 5 × 10(-8) ) gene-by-sex interaction in the joint analysis of discovery and replication cohorts. Despite the large collaborative effort, no genome-wide significant evidence for gene-by-sex interaction was found to influence BMD variation in this screen of autosomal markers. If they exist, gene-by-sex interactions for BMD probably have weak effects, accounting for less than 0.08% of the variation in these traits per implicated SNP. © 2012 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.1679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3447125PMC
October 2012

Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture.

Nat Genet 2012 Apr 15;44(5):491-501. Epub 2012 Apr 15.

Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.

Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.
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http://dx.doi.org/10.1038/ng.2249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3338864PMC
April 2012

Association of CLU and PICALM variants with Alzheimer's disease.

Neurobiol Aging 2012 Mar 8;33(3):518-21. Epub 2010 Jun 8.

Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA 15261, United States.

Two recent large genome-wide association studies have reported significant associations in the CLU (APOJ), CR1, and PICALM genes with the risk of Alzheimer's disease (AD). In order to replicate these findings, we examined 7 single nucleotide polymorphisms (SNPs) most significantly implicated by these studies in a large case-control sample comprising 2707 individuals. Principle components analysis revealed no population substructure in our sample. While no association was observed with CR1 SNPs (p = 0.30-0.457), a trend of association was seen with the PICALM (p = 0.071-0.086) and CLU (p = 0.148-0.258) SNPs. A meta-analysis of 3 studies revealed significant associations with all 3 genes. Our data from an independent and large case-control sample suggest that these gene regions should be followed up by comprehensive resequencing to find functional variants.
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http://dx.doi.org/10.1016/j.neurobiolaging.2010.04.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3010357PMC
March 2012
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