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1.  Genetic Variation at NCAN Locus is Associated with Inflammation and Fibrosis in Non-alcoholic Fatty Liver Disease in Morbid Obesity 
Human heredity  2013;75(1):10.1159/000346195.
Obesity-associated non-alcoholic fatty liver disease (NAFLD) may cause liver dysfunction and failure. In a previously reported genome-wide association meta-analysis, single nucleotide polymorphisms (SNPs) near PNPLA3, NCAN, GCKR, LYPLAL1 and PPP1R3B were associated with NAFLD and with distinctive serum lipid profiles. The present study examined the relevance of these variants to NAFLD in extreme obesity.
In 1,092 bariatric patients, the candidate SNPs were genotyped and association analyses with liver histology and serum lipids were performed.
We replicated the association of hepatosteatosis with PNPLA3 rs738409[G] and with NCAN rs2228603[T]. We also replicated the association of rs2228603[T] with hepatic inflammation and fibrosis. Rs2228603[T] was associated with lower serum LDL, total cholesterol and triglycerides. After stratification by the presence or absence of NAFLD, these associations were present predominantly in the subgroup with NAFLD.
NCAN rs2228603[T] is a risk factor for liver inflammation and fibrosis, suggesting that this locus is responsible for progression from steatosis to steatohepatitis. In this bariatric cohort, rs2228603[T] was associated with low serum lipids only in patients with NAFLD. This supports a NAFLD model in which the liver may sequester triglycerides as a result of either increased triglyceride uptake and/or decreased lipolysis.
PMCID: PMC3864002  PMID: 23594525
Obesity; dyslipidemia; steatohepatitis; cirrhosis; steatosis
2.  Identification of Nine Novel Loci Associated with White Blood Cell Subtypes in a Japanese Population 
PLoS Genetics  2011;7(6):e1002067.
White blood cells (WBCs) mediate immune systems and consist of various subtypes with distinct roles. Elucidation of the mechanism that regulates the counts of the WBC subtypes would provide useful insights into both the etiology of the immune system and disease pathogenesis. In this study, we report results of genome-wide association studies (GWAS) and a replication study for the counts of the 5 main WBC subtypes (neutrophils, lymphocytes, monocytes, basophils, and eosinophils) using 14,792 Japanese subjects enrolled in the BioBank Japan Project. We identified 12 significantly associated loci that satisfied the genome-wide significance threshold of P<5.0×10−8, of which 9 loci were novel (the CDK6 locus for the neutrophil count; the ITGA4, MLZE, STXBP6 loci, and the MHC region for the monocyte count; the SLC45A3-NUCKS1, GATA2, NAALAD2, ERG loci for the basophil count). We further evaluated associations in the identified loci using 15,600 subjects from Caucasian populations. These WBC subtype-related loci demonstrated a variety of patterns of pleiotropic associations within the WBC subtypes, or with total WBC count, platelet count, or red blood cell-related traits (n = 30,454), which suggests unique and common functional roles of these loci in the processes of hematopoiesis. This study should contribute to the understanding of the genetic backgrounds of the WBC subtypes and hematological traits.
Author Summary
White blood cells (WBCs) are blood cells that mediate immune systems and defend the body against foreign microorganisms. It is well known that WBCs consist of various subtypes of cells with distinct roles, although the genetic background of each of the WBC subtypes has yet to be examined. In this study, we report genome-wide association studies (GWAS) for the 5 main WBC subtypes (neutrophils, lymphocytes, monocytes, basophils, and eosinophils) using 14,792 Japanese subjects. We identified 12 significantly associated genetic loci, and 9 of them were novel. Evaluation of the associations of these identified loci in cohorts of Caucasian populations demonstrated both ethnically common and divergent genetic backgrounds of the WBC subtypes. These loci also indicated a variety of patterns of pleiotropic associations within the hematological traits, including the other WBC subtypes, total WBC count, platelet count, or red blood cell-related traits, which suggests unique and common functional roles of these loci in the processes of hematopoiesis.
PMCID: PMC3128095  PMID: 21738478
3.  Age, Gene/Environment Susceptibility – Reykjavik Study: Multidisciplinary Applied Phenomics 
American journal of epidemiology  2007;165(9):1076-1087.
Anticipating the sequencing of the human genome and description of the human proteome, the Age, Gene/Environment Susceptibility-Reykjavik Study (AGES-Reykjavik) was initiated in 2002. AGES-Reykjavik was designed to examine risk factors, including genetic susceptibility and gene/environment interaction, in relation to disease and disability in old age. The study is multidisciplinary, providing detailed phenotypes related to the cardiovascular, neurocognitive (including sensory), and musculoskeletal systems, and to body composition and metabolic regulation. Relevant quantitative traits, subclinical indicators of disease, and medical diagnoses are identified using biomarkers, imaging, and other physiologic indicators. The AGES-Reykjavik sample is drawn from an established population-based cohort, the Reykjavik Study. This cohort of men and women born between 1907 and 1935 has been followed in Iceland since 1967 by the Icelandic Heart Association. The AGES-Reykjavik cohort, with cardiovascular risk factor assessments earlier in life and detailed late life phenotypes of quantitative traits, will create a comprehensive study of aging nested in a relatively genetically homogeneous older population. This approach should facilitate identification of genetic factors that contribute to healthy aging as well as the chronic conditions common in old age.
PMCID: PMC2723948  PMID: 17351290
Aging; Population Genetics; Phenotype; Epidemiology; Cognition; Cardiovascular Disease; Osteoporosis; Body composition
4.  Association Between Cerebellar Gray Matter Volumes, Gait Speed, and Information-Processing Ability in Older Adults Enrolled in the Health ABC Study 
The cerebellum plays an important role in mobility and cognition. However, it is unclear which regions of the cerebellum are associated with gait speed and information-processing ability in older adults without overt brain damage.
Cross-sectional associations between cerebellar gray matter volumes (GMV), gait speed, and information-processing ability were explored in 231 community-dwelling adults (mean age: 83 years, 48% black, 58% female). We measured gait speed on an automated walkway and information-processing ability on the Digit Symbol Substitution test (DSST). Total and regional cerebellar GMV was measured on 3T-magnetic resonance imaging. Lobar GMV of the cerebellum, obtained by an automated parcellation process, were aggregated based on the cognitive (lobules VI, VII, VIII and crus I, II), sensorimotor (lobules II, IV, V), and vestibular (lobules IX and X) functions ascribed to the cerebellar regions.
Larger cerebellar GMV correlated with faster gait speed and superior DSST scores (both p < .001) independent of age, gender, atrophy, and small vessel disease. After adjusting for age, gender, and atrophy, larger cognitive cerebellar GMV correlated with both faster gait speed (p = .04) and higher DSST scores (p < .001), larger sensorimotor cerebellar GMV correlated significantly with DSST alone (p = .02), and the vestibular cerebellar GMV with neither. The association between cognitive cerebellar GMV and gait speed was no longer significant after adjusting for DSST score in the linear regression models.
The relationship between gait speed and cerebellar GMV is influenced by information-processing ability, and this relationship is stronger in subregions ascribed to cognitive than vestibular or sensorimotor functions.
PMCID: PMC4095927  PMID: 24170673
Gait; Brain aging; Cognition; Imaging.
5.  Weight Change, Body Composition and Risk of Mobility Disability and Mortality in Older Adults:A Population Based Cohort Study 
To examine associations between weight change, body composition, risk of mobility disability and mortality in older adults.
Prospective, longitudinal, population-based cohort.
The Health ABC Study.
Women (n=1044) and men (n=931) aged 70-79.
Weight,lean and fat mass from DXA measured annually over 5 years. Weight was defined as stable (n=664, referent group), loss (n=662), gain (n=321) or cycling (gain and loss, n=328) using change of 5% from year to year or from year 1 to 6. Mobility disability (two consecutive reports of difficulty walking one-quarter mile or climbing 10 steps) and mortality were determined for 8 years subsequent to the weight change period. Associations were analyzed with cox proportional hazards regression adjusted for covariates.
During follow-up, 313 women and 375 men developed mobility disability,322 women and 378 men were deceased. There was no risk of mobility disability or mortality with weight gain. Weight loss and weight cycling were associated with mobility disability in women:hazard ratio (HR)=1.88 (95% confidence interval (CI)=1.40-2.53),HR=1.59 (95% CI=1.11-2.29) and weight loss was associated in men:HR=1.30 (95% CI=1.01-1.69).Weight loss and weight cycling were associated with mortality risk in women:HR=1.47 (95% CI=1.07-2.01), HR=1.62 (95% CI=1.15-2.30) and in men:HR=1.41 (95% CI=1.09-1.83),HR=1.50 (95% CI=1.08-2.08). Adjustment for lean and fat mass and change in lean and fat mass from year 1 to 6 attenuated relationships between weight loss and mobility disability in men, and weight loss and mortality in men and women.
Weight cycling and weight loss predict impendingmobility disability and mortality in old age, underscoring the prognostic importance of weight history.
PMCID: PMC4134405  PMID: 25039391
Aging; obesity; physical function; body composition; muscle loss
6.  Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility 
Wessel, Jennifer | Chu, Audrey Y. | Willems, Sara M. | Wang, Shuai | Yaghootkar, Hanieh | Brody, Jennifer A. | Dauriz, Marco | Hivert, Marie-France | Raghavan, Sridharan | Lipovich, Leonard | Hidalgo, Bertha | Fox, Keolu | Huffman, Jennifer E. | An, Ping | Lu, Yingchang | Rasmussen-Torvik, Laura J. | Grarup, Niels | Ehm, Margaret G. | Li, Li | Baldridge, Abigail S. | Stančáková, Alena | Abrol, Ravinder | Besse, Céline | Boland, Anne | Bork-Jensen, Jette | Fornage, Myriam | Freitag, Daniel F. | Garcia, Melissa E. | Guo, Xiuqing | Hara, Kazuo | Isaacs, Aaron | Jakobsdottir, Johanna | Lange, Leslie A. | Layton, Jill C. | Li, Man | Zhao, Jing Hua | Meidtner, Karina | Morrison, Alanna C. | Nalls, Mike A. | Peters, Marjolein J. | Sabater-Lleal, Maria | Schurmann, Claudia | Silveira, Angela | Smith, Albert V. | Southam, Lorraine | Stoiber, Marcus H. | Strawbridge, Rona J. | Taylor, Kent D. | Varga, Tibor V. | Allin, Kristine H. | Amin, Najaf | Aponte, Jennifer L. | Aung, Tin | Barbieri, Caterina | Bihlmeyer, Nathan A. | Boehnke, Michael | Bombieri, Cristina | Bowden, Donald W. | Burns, Sean M. | Chen, Yuning | Chen, Yii-Der I. | Cheng, Ching-Yu | Correa, Adolfo | Czajkowski, Jacek | Dehghan, Abbas | Ehret, Georg B. | Eiriksdottir, Gudny | Escher, Stefan A. | Farmaki, Aliki-Eleni | Frånberg, Mattias | Gambaro, Giovanni | Giulianini, Franco | III, William A. Goddard | Goel, Anuj | Gottesman, Omri | Grove, Megan L. | Gustafsson, Stefan | Hai, Yang | Hallmans, Göran | Heo, Jiyoung | Hoffmann, Per | Ikram, Mohammad K. | Jensen, Richard A. | Jørgensen, Marit E. | Jørgensen, Torben | Karaleftheri, Maria | Khor, Chiea C. | Kirkpatrick, Andrea | Kraja, Aldi T. | Kuusisto, Johanna | Lange, Ethan M. | Lee, I.T. | Lee, Wen-Jane | Leong, Aaron | Liao, Jiemin | Liu, Chunyu | Liu, Yongmei | Lindgren, Cecilia M. | Linneberg, Allan | Malerba, Giovanni | Mamakou, Vasiliki | Marouli, Eirini | Maruthur, Nisa M. | Matchan, Angela | McKean, Roberta | McLeod, Olga | Metcalf, Ginger A. | Mohlke, Karen L. | Muzny, Donna M. | Ntalla, Ioanna | Palmer, Nicholette D. | Pasko, Dorota | Peter, Andreas | Rayner, Nigel W. | Renström, Frida | Rice, Ken | Sala, Cinzia F. | Sennblad, Bengt | Serafetinidis, Ioannis | Smith, Jennifer A. | Soranzo, Nicole | Speliotes, Elizabeth K. | Stahl, Eli A. | Stirrups, Kathleen | Tentolouris, Nikos | Thanopoulou, Anastasia | Torres, Mina | Traglia, Michela | Tsafantakis, Emmanouil | Javad, Sundas | Yanek, Lisa R. | Zengini, Eleni | Becker, Diane M. | Bis, Joshua C. | Brown, James B. | Cupples, L. Adrienne | Hansen, Torben | Ingelsson, Erik | Karter, Andrew J. | Lorenzo, Carlos | Mathias, Rasika A. | Norris, Jill M. | Peloso, Gina M. | Sheu, Wayne H.-H. | Toniolo, Daniela | Vaidya, Dhananjay | Varma, Rohit | Wagenknecht, Lynne E. | Boeing, Heiner | Bottinger, Erwin P. | Dedoussis, George | Deloukas, Panos | Ferrannini, Ele | Franco, Oscar H. | Franks, Paul W. | Gibbs, Richard A. | Gudnason, Vilmundur | Hamsten, Anders | Harris, Tamara B. | Hattersley, Andrew T. | Hayward, Caroline | Hofman, Albert | Jansson, Jan-Håkan | Langenberg, Claudia | Launer, Lenore J. | Levy, Daniel | Oostra, Ben A. | O'Donnell, Christopher J. | O'Rahilly, Stephen | Padmanabhan, Sandosh | Pankow, James S. | Polasek, Ozren | Province, Michael A. | Rich, Stephen S. | Ridker, Paul M | Rudan, Igor | Schulze, Matthias B. | Smith, Blair H. | Uitterlinden, André G. | Walker, Mark | Watkins, Hugh | Wong, Tien Y. | Zeggini, Eleftheria | Scotland, Generation | Laakso, Markku | Borecki, Ingrid B. | Chasman, Daniel I. | Pedersen, Oluf | Psaty, Bruce M. | Tai, E. Shyong | van Duijn, Cornelia M. | Wareham, Nicholas J. | Waterworth, Dawn M. | Boerwinkle, Eric | Kao, WH Linda | Florez, Jose C. | Loos, Ruth J.F. | Wilson, James G. | Frayling, Timothy M. | Siscovick, David S. | Dupuis, Josée | Rotter, Jerome I. | Meigs, James B. | Scott, Robert A. | Goodarzi, Mark O.
Nature communications  2015;6:5897.
Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=-0.09±0.01 mmol L−1, p=3.4×10−12), T2D risk (OR[95%CI]=0.86[0.76-0.96], p=0.010), early insulin secretion (β=-0.07±0.035 pmolinsulin mmolglucose−1, p=0.048), but higher 2-h glucose (β=0.16±0.05 mmol L−1, p=4.3×10−4). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8×10−6) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol L−1, p=1.3×10−8). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.
PMCID: PMC4311266  PMID: 25631608
7.  Midlife Determinants Associated with Sedentary Behavior in Old Age 
Sedentary behavior is associated with adverse health effects. To prevent sedentary behavior and limit health risks, insights into associated determinants are essential. Sedentary behavior should be viewed as a distinct health behavior, therefore its determinants should be independently identified.
This study examines the prospective associations between a wide-range of midlife determinants and objectively measured sedentary time in old age.
Data from 565 participants (aged 73–92 years) of the AGESII-Reykjavik Study were used. Participants wore an accelerometer (ActiGraph GT3X) on the right hip for 7 consecutive days. On average 31 years earlier (during midlife) demographic, socioeconomic, lifestyle and biomedical factors were collected. Linear regression models were used to examine prospective associations between midlife determinants and sedentary time (<100 counts per minute) in old age.
After adjustment for sex, age, follow-up time, minutes of moderate to vigorous physical activity, BMI, health status, mobility limitation and joint pain in old age, the midlife determinants not being married, primary education, living in a duplex or living in an apartment (vs. villa), being obese and having a heart disease were associated with, respectively, on average 15.3, 12.4, 13.5, 13.3, 21.8, 38.9 sedentary minutes more per day in old age.
This study shows that demographic, socioeconomic and biomedical determinants in midlife were associated with considerably more sedentary time per day in old age. These results can indicate the possibility of predicting sedentariness in old age, which could be used to identify target groups for prevention programs reducing sedentary time in older adults.
PMCID: PMC4061270  PMID: 24389522
Accelerometry; Sedentary Lifestyle; Older Adults; Longitudinal Studies; Socioeconomic Factors; Biomedical Factors
8.  Older Adults With Limited Literacy Are at Increased Risk for Likely Dementia 
Low literacy is common among the elderly and possibly more reflective of educational attainment than years of school completed. We examined the association between literacy and risk of likely dementia in older adults.
Participants were 2,458 black and white elders (aged 71–82) from the Health, Aging and Body Composition study, who completed the Rapid Estimate of Adult Literacy in Medicine and were followed for 8 years. Participants were free of dementia at baseline; incidence of likely dementia was defined by hospital records, prescription for dementia medication, or decline in Modified Mini-Mental State Examination score. We conducted Cox proportional hazard models to evaluate the association between literacy and incidence of likely dementia. Demographics, education, income, comorbidities, lifestyle variables, and apolipoprotein E (APOE) ε4 status were included in adjusted analyses.
Twenty-three percent of participants had limited literacy (<9th-grade level). Limited literacy, as opposed to adequate literacy (≥9th-grade level), was associated with greater incidence of likely dementia (25.5% vs17.0%; unadjusted hazard ratio [HR] = 1.75, 95% confidence interval 1.44–2.13); this association remained significant after adjustment. There was a trend for an interaction between literacy and APOE ε4 status (p = .07); the association between limited literacy and greater incidence of likely dementia was strong among ε4 noncarriers (unadjusted HR = 1.85) but nonsignificant among ε4 carriers (unadjusted HR = 1.25).
Limited literacy is an important risk factor for likely dementia, especially among APOE ε4-negative older adults, and may prove fruitful to target in interventions aimed at reducing dementia risk.
PMCID: PMC4067115  PMID: 24158765
Cognitive aging; Risk factors; Epidemiology.
9.  Changes in Daily Activity Patterns with Age among US Men and Women: NHANES 2003–2004 and 2005–2006 
Men achieve more moderate-to-vigorous physical activity (MPVA) than women, yet with advancing age men become more sedentary than women. No study has comprehensively assessed this change in activity pattern. We compare daily and hourly activity patterns by gender and age.
Cross-sectional; Observational
Nationally-representative community sample: NHANES 2003–2004; 2005–2006
Accelerometer data from respondents (n=5,788) aged ≥20 years with 4+ valid days of monitor wear-time, no missing data on valid wear-time minutes, and covariates.
Activity was examined as average counts per minute (CPM) during wear-time, percentage of time spent in non-sedentary activity, and time (minutes) spent in sedentary (<100 counts); light (100–759); MVPA (≥760) intensity levels. Analyses accounted for survey design, adjusted for covariates and were gender specific.
In adjusted models, men spent slightly greater time (~1–2%) in non-sedentary activity than women 20–34y, with levels converging at 35–59y, though a non-significant difference. Women age ≥60 spent significantly greater time (~3–4%) in non-sedentary activity than men, despite similarly achieved average CPM. With increasing age, all non-sedentary activity decreased in men; levels of light-activity remained constant among women (~30%). Older men had fewer CPM at night (~20 CPM), more daytime sedentary minutes (~3), fewer daytime light minutes (~4), and more MVPA minutes (~1) until early evening, than older women.
While gender differences in average CPM reduced with age, differences in non-sedentary activity time emerged as men increased sedentary behavior and reduced MVPA time. Maintained levels of light-intensity activity suggest women continue engaging in common daily activities into older-age more often than men. Findings may help inform the development of behavioral interventions to increase intensity and overall activity levels, particularly among older adults.
PMCID: PMC4115191  PMID: 24962323
NHANES 2003–2004, 2005–2006; Physical activity; Sedentary behavior; Accelerometer; Patterns of daily activity
10.  Classification of occupational activity categories using accelerometry: NHANES 2003–2004 
An individual’s occupational activity (OA) may contribute significantly to daily physical activity (PA) and sedentary behavior (SB). However, there is little consensus about which occupational categories involve high OA or low OA, and the majority of categories are unclassifiable with current methods. The purpose of this study was to present population estimates of accelerometer-derived PA and SB variables for adults (n = 1112, 20–60 years) working the 40 occupational categories collected during the 2003–2004 National Health and Nutrition Examination Survey (NHANES).
ActiGraph accelerometer-derived total activity counts/day (TAC), activity counts/minute, and proportion of wear time spent in moderate-to-vigorous PA [MVPA], lifestyle, and light PA organized by occupational category were ranked in ascending order and SB was ranked in descending order. Summing the ranks of the six accelerometer-derived variables generated a summary score for each occupational category, which was re-ranked in ascending order. Higher rankings indicated higher levels of OA, lower rankings indicated lower levels of OA. Tertiles of the summary score were used to establish three mutually exclusive accelerometer-determined OA groupings: high OA, intermediate OA, and low OA.
According to their summary score, ‘farm and nursery workers’ were classified as high OA and ‘secretaries, stenographers, and typists’ were classified as low OA. Consistent with previous research, some low OA occupational categories (e.g., ‘engineers, architects, and scientists’, ‘technicians and related support occupations’, ‘management related occupations’, ‘executives, administrators, and managers’, ‘protective services’, and ‘writers, artists, entertainers, and athletes’) associated with higher education and income had relatively greater amounts of MVPA compared to other low OA occupational categories, likely due to the greater percentage of men in those occupations and/or the influence of higher levels of leisure time PA. Men had more TAC, activity counts/minute and time in MVPA, but similar proportions of SB compared to women in all three OA groupings.
Objectively measured PA allowed for a more precise estimate of the amount of PA and SB associated with different occupations and facilitated systematic classification of the 40 different occupational categories into three distinct OA groupings. This information provides new opportunities to explore the relationship between OA and health outcomes.
PMCID: PMC4499449  PMID: 26122724
Occupational activity; Accelerometer; Work; Employment; Classification; Cross-sectional
11.  Joint effect of mid- and late-life blood pressure on the brain 
Neurology  2014;82(24):2187-2195.
We hypothesized that in participants with a history of hypertension, lower late-life blood pressure (BP) will be associated with more brain pathology.
Participants are 4,057 older men and women without dementia with midlife (mean age 50 ± 6 years) and late-life (mean age 76 ± 5 years) vascular screening, cognitive function, and brain structures on MRI ascertained as part of the Age, Gene/Environment Susceptibility (AGES)–Reykjavik Study.
The association of late-life BP to brain measures depended on midlife hypertension history. Higher late-life systolic and diastolic BP (DBP) was associated with an increased risk of white matter lesions and cerebral microbleeds, and this was most pronounced in participants without a history of midlife hypertension. In contrast, in participants with a history of midlife hypertension, lower late-life DBP was associated with smaller total brain and gray matter volumes. This finding was reflected back in cognitive performance; in participants with midlife hypertension, lower DBP was associated with lower memory scores.
In this large population-based cohort, late-life BP differentially affects brain pathology and cognitive performance, depending on the history of midlife hypertension. Our study suggests history of hypertension is critical to understand how late-life BP affects brain structure and function.
PMCID: PMC4113458  PMID: 24898928
12.  Meta-analysis of loci associated with age at natural menopause in African-American women 
Human Molecular Genetics  2014;23(12):3327-3342.
Age at menopause marks the end of a woman's reproductive life and its timing associates with risks for cancer, cardiovascular and bone disorders. GWAS and candidate gene studies conducted in women of European ancestry have identified 27 loci associated with age at menopause. The relevance of these loci to women of African ancestry has not been previously studied. We therefore sought to uncover additional menopause loci and investigate the relevance of European menopause loci by performing a GWAS meta-analysis in 6510 women with African ancestry derived from 11 studies across the USA. We did not identify any additional loci significantly associated with age at menopause in African Americans. We replicated the associations between six loci and age at menopause (P-value < 0.05): AMHR2, RHBLD2, PRIM1, HK3/UMC1, BRSK1/TMEM150B and MCM8. In addition, associations of 14 loci are directionally consistent with previous reports. We provide evidence that genetic variants influencing reproductive traits identified in European populations are also important in women of African ancestry residing in USA.
PMCID: PMC4030781  PMID: 24493794
13.  Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium 
Moayyeri, Alireza | Hsu, Yi-Hsiang | Karasik, David | Estrada, Karol | Xiao, Su-Mei | Nielson, Carrie | Srikanth, Priya | Giroux, Sylvie | Wilson, Scott G. | Zheng, Hou-Feng | Smith, Albert V. | Pye, Stephen R. | Leo, Paul J. | Teumer, Alexander | Hwang, Joo-Yeon | Ohlsson, Claes | McGuigan, Fiona | Minster, Ryan L. | Hayward, Caroline | Olmos, José M. | Lyytikäinen, Leo-Pekka | Lewis, Joshua R. | Swart, Karin M.A. | Masi, Laura | Oldmeadow, Chris | Holliday, Elizabeth G. | Cheng, Sulin | van Schoor, Natasja M. | Harvey, Nicholas C. | Kruk, Marcin | del Greco M, Fabiola | Igl, Wilmar | Trummer, Olivia | Grigoriou, Efi | Luben, Robert | Liu, Ching-Ti | Zhou, Yanhua | Oei, Ling | Medina-Gomez, Carolina | Zmuda, Joseph | Tranah, Greg | Brown, Suzanne J. | Williams, Frances M. | Soranzo, Nicole | Jakobsdottir, Johanna | Siggeirsdottir, Kristin | Holliday, Kate L. | Hannemann, Anke | Go, Min Jin | Garcia, Melissa | Polasek, Ozren | Laaksonen, Marika | Zhu, Kun | Enneman, Anke W. | McEvoy, Mark | Peel, Roseanne | Sham, Pak Chung | Jaworski, Maciej | Johansson, Åsa | Hicks, Andrew A. | Pludowski, Pawel | Scott, Rodney | Dhonukshe-Rutten, Rosalie A.M. | van der Velde, Nathalie | Kähönen, Mika | Viikari, Jorma S. | Sievänen, Harri | Raitakari, Olli T. | González-Macías, Jesús | Hernández, Jose L. | Mellström, Dan | Ljunggren, Östen | Cho, Yoon Shin | Völker, Uwe | Nauck, Matthias | Homuth, Georg | Völzke, Henry | Haring, Robin | Brown, Matthew A. | McCloskey, Eugene | Nicholson, Geoffrey C. | Eastell, Richard | Eisman, John A. | Jones, Graeme | Reid, Ian R. | Dennison, Elaine M. | Wark, John | Boonen, Steven | Vanderschueren, Dirk | Wu, Frederick C.W. | Aspelund, Thor | Richards, J. Brent | Bauer, Doug | Hofman, Albert | Khaw, Kay-Tee | Dedoussis, George | Obermayer-Pietsch, Barbara | Gyllensten, Ulf | Pramstaller, Peter P. | Lorenc, Roman S. | Cooper, Cyrus | Kung, Annie Wai Chee | Lips, Paul | Alen, Markku | Attia, John | Brandi, Maria Luisa | de Groot, Lisette C.P.G.M. | Lehtimäki, Terho | Riancho, José A. | Campbell, Harry | Liu, Yongmei | Harris, Tamara B. | Akesson, Kristina | Karlsson, Magnus | Lee, Jong-Young | Wallaschofski, Henri | Duncan, Emma L. | O'Neill, Terence W. | Gudnason, Vilmundur | Spector, Timothy D. | Rousseau, François | Orwoll, Eric | Cummings, Steven R. | Wareham, Nick J. | Rivadeneira, Fernando | Uitterlinden, Andre G. | Prince, Richard L. | Kiel, Douglas P. | Reeve, Jonathan | Kaptoge, Stephen K.
Human Molecular Genetics  2014;23(11):3054-3068.
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.
PMCID: PMC4038791  PMID: 24430505
14.  Transition to Sarcopenia and Determinants of Transitions in Older Adults: A Population-Based Study 
Diagnostic criteria for sarcopenia from appendicular lean mass (ALM), strength, and performance have been proposed, but little is known regarding the progression of sarcopenia.
We examined the time course of sarcopenia and determinants of transitioning toward and away from sarcopenia.
ALM, gait speed, and grip strength were assessed seven times over 9 years in 2,928 initially well-functioning adults aged 70–79. Low ALM was defined as less than 7.95 kg/m2 (men) or less than 6.24 kg/m2 (women), low performance as gait speed less than 1.0 m/s, low strength as grip strength less than 30 kg (men) or less than 20 kg (women). Presarcopenia was defined as low ALM and sarcopenia as low ALM with low performance or low strength. Hidden Markov modeling was used to characterize states of ALM, strength, and performance and model transitions leading to sarcopenia and death. Determinants of transitioning toward and away from sarcopenia were examined with logistic regression.
Initially, 54% of participants had normal ALM, strength, and performance; 21% had presarcopenia; 5% had sarcopenia; and 20% had intermediate characteristics. Of participants with normal ALM, strength, and performance, 1% transitioned to presarcopenia and none transitioned to sarcopenia. The greatest transition to sarcopenia (7%) was in presarcopenic individuals. Low-functioning and sarcopenia states were more likely to lead to death (12% and 13%). Higher body mass index (p < .001) and pain (p = .05) predicted transition toward sarcopenia, whereas moderate activity predicted transition from presarcopenia to more normal states (p = .02).
Pain, physical activity, and body mass index, potentially modifiable factors, are determinants of transitions. Promotion of health approaching old age is important as few individuals transition away from their initial state.
PMCID: PMC4022098  PMID: 24013673
Muscle; Aging; Physical function; Sarcopenia; Epidemiology.
15.  Three Authors Reply 
American Journal of Epidemiology  2014;179(11):1403-1404.
PMCID: PMC4047278  PMID: 24786798
16.  Insulin-like growth factor-1 and risk of Alzheimer dementia and brain atrophy 
Neurology  2014;82(18):1613-1619.
To relate serum insulin-like growth factor-1 (IGF-1) to risk of Alzheimer disease (AD) dementia and to brain volumes in a dementia-free community sample spanning middle and older ages.
Dementia-free Framingham participants from generation 1 (n = 789, age 79 ± 4 years, 64% women) and generation 2 (n = 2,793, age 61 ± 9 years, 55% women; total = 3,582, age 65 ± 11 years, 57% women) had serum IGF-1 measured in 1990–1994 and 1998–2001, respectively, and were followed prospectively for incident dementia and AD dementia. Brain MRI was obtained in stroke- and dementia-free survivors of both generations 1 (n = 186) and 2 (n = 1,867) during 1999–2005. Baseline IGF-1 was related to risk of incident dementia using Cox models and to total brain and hippocampal volumes using linear regression in multivariable models adjusted for age, sex, APOE ε4, plasma homocysteine, waist-hip ratio, and physical activity.
Mean IGF-1 levels were 144 ± 60 μg/L in generation 1 and 114 ± 37 μg/L in generation 2. We observed 279 cases of incident dementia (230 AD dementia) over a mean follow-up of 7.4 ± 3.1 years. Persons with IGF-1 in the lowest quartile had a 51% greater risk of AD dementia (hazard ratio = 1.51, 95% confidence interval: 1.14–2.00; p = 0.004). Among persons without dementia, higher IGF-1 levels were associated with greater total brain volumes (β/SD increment in IGF-1 was 0.55 ± 0.24, p = 0.025; and 0.26 ± 0.06, p < 0.001, for generations 1 and 2, respectively).
Lower serum levels of IGF-1 are associated with an increased risk of developing AD dementia and higher levels with greater brain volumes even among middle-aged community-dwelling participants free of stroke and dementia. Higher levels of IGF-1 may protect against subclinical and clinical neurodegeneration.
PMCID: PMC4013812  PMID: 24706014
17.  Structural MRI correlates of apathy symptoms in older persons without dementia 
Neurology  2014;82(18):1628-1635.
We aimed to investigate the relation between apathy symptoms and structural brain changes on MRI, including white matter lesions (WMLs) and atrophy, in a large cohort of older persons.
Cross-sectional analyses are based on 4,354 persons without dementia (aged 76 ± 5 years) participating in the population-based Age, Gene/Environment Susceptibility–Reykjavik Study. Apathy symptoms were assessed with 3 items from the 15-item Geriatric Depression Scale. Brain volumes and total WML volume were estimated on 1.5-tesla MRI using an automated segmentation program; regional WML load was calculated using a semiquantitative scale. Regression analyses were adjusted for age, sex, education, intracranial volume, vascular risk factors, physical activity, brain infarcts, depressive symptoms, antidepressants, and cognitive status.
Compared to those with <2 apathy symptoms, participants with ≥2 apathy symptoms (49% of the cohort) had significantly smaller gray matter volumes (mean adjusted difference −3.6 mL, 95% confidence interval [CI] −6.2 to −1.0), particularly in the frontal and temporal lobes; smaller white matter volumes (mean adjusted difference −1.9 mL, 95% CI −3.6 to −0.3), mainly in the parietal lobe; and smaller thalamus volumes. They were also more likely to have WMLs in the frontal lobe (adjusted odds ratio = 1.08, 95% CI 0.9–1.3). Excluding participants with a depression diagnosis did not change the associations.
In this older population without dementia, apathy symptoms are associated with a more diffuse loss of both gray and white matter volumes, independent of depression.
PMCID: PMC4013817  PMID: 24739783
18.  Association of Low-Density Lipoprotein Cholesterol–Related Genetic Variants With Aortic Valve Calcium and Incident Aortic Stenosis 
JAMA  2014;312(17):1764-1771.
Plasma low-density lipoprotein cholesterol (LDL-C) has been associated with aortic stenosis in observational studies; however, randomized trials with cholesterol-lowering therapies in individuals with established valve disease have failed to demonstrate reduced disease progression.
To evaluate whether genetic data are consistent with an association between LDL-C, high-density lipoprotein cholesterol (HDL-C), or triglycerides (TG) and aortic valve disease.
Using a Mendelian randomization study design, we evaluated whether weighted genetic risk scores (GRSs), a measure of the genetic predisposition to elevations in plasma lipids, constructed using single-nucleotide polymorphisms identified in genome-wide association studies for plasma lipids, were associated with aortic valve disease. We included community-based cohorts participating in the CHARGE consortium (n = 6942), including the Framingham Heart Study (cohort inception to last follow-up: 1971-2013; n = 1295), Multi-Ethnic Study of Atherosclerosis (2000-2012; n = 2527), Age Gene/Environment Study-Reykjavik (2000-2012; n = 3120), and the Malmö Diet and Cancer Study (MDCS, 1991-2010; n = 28 461).
Aortic valve calcium quantified by computed tomography in CHARGE and incident aortic stenosis in the MDCS.
The prevalence of aortic valve calcium across the 3 CHARGE cohorts was 32% (n = 2245). In the MDCS, over a median follow-up time of 16.1 years, aortic stenosis developed in 17 per 1000 participants (n = 473) and aortic valve replacement for aortic stenosis occurred in 7 per 1000 (n = 205). Plasma LDL-C, but not HDL-C or TG, was significantly associated with incident aortic stenosis (hazard ratio [HR] per mmol/L, 1.28; 95% CI, 1.04-1.57; P = .02; aortic stenosis incidence: 1.3% and 2.4% in lowest and highest LDL-C quartiles, respectively). The LDL-C GRS, but not HDL-C or TG GRS, was significantly associated with presence of aortic valve calcium in CHARGE (odds ratio [OR] per GRS increment, 1.38; 95% CI, 1.09-1.74; P = .007) and with incident aortic stenosis in MDCS (HR per GRS increment, 2.78; 95% CI, 1.22-6.37; P = .02; aortic stenosis incidence: 1.9% and 2.6% in lowest and highest GRS quartiles, respectively). In sensitivity analyses excluding variants weakly associated with HDL-C or TG, the LDL-C GRS remained associated with aortic valve calcium (P = .03) and aortic stenosis (P = .009). In instrumental variable analysis, LDL-C was associated with an increase in the risk of incident aortic stenosis (HR per mmol/L, 1.51; 95% CI, 1.07-2.14; P = .02).
Genetic predisposition to elevated LDL-C was associated with presence of aortic valve calcium and incidence of aortic stenosis, providing evidence supportive of a causal association between LDL-C and aortic valve disease. Whether earlier intervention to reduce LDL-C could prevent aortic valve disease merits further investigation.
PMCID: PMC4280258  PMID: 25344734
19.  Comparison Between Southern Blots and qPCR Analysis of Leukocyte Telomere Length in the Health ABC Study 
Only a few studies, primarily limited to small samples, have examined the relationship between leukocyte telomere length (LTL) data generated by Southern blots, expressed in kilobases, versus quantitative PCR data, expressed in the telomere product/a single gene product (T/S). In the present study, we compared LTL data generated by the two methods in 681 elderly participants (50% African Americans, 50% of European origin, 49.2% women, mean age 73.7±2.9 years) in the Health Aging and Body Composition Study. The correlation between the data generated by the two methods was modest (R 2 = .27). Both methods captured the age effect on LTL and the longer LTL in women than in men. However, only the Southern blot method showed a significantly longer LTL in African Americans than in European decent individuals, which might be attributed to the larger measurement error of the quantitative PCR–based method than the Southern blots.
PMCID: PMC4049151  PMID: 23946336
Leukocyte telomere length; Quantitative PCR; Southern blots.
20.  Higher Step Length Variability Indicates Lower Grey Matter Integrity of Selected Regions in Older Adults 
Gait & posture  2014;40(1):225-230.
Step length variability (SLV) increases with age in those without overt neurologic disease, is higher in neurologic patients, is associated with falls, and predicts dementia. Whether higher SLV in older adults without neurologic disease indicates presence of neurologic abnormalities is unknown. Our objective was to identify whether SLV in older adults without overt disease is associated with findings from multimodal neuroimaging. A well-characterized cohort of 265 adults (79–90 years) was concurrently assessed by gait mat, magnetic resonance imaging with diffusion tensor, and neurological exam. Linear regression models adjusted for gait speed, demographic, health, and functional covariates assessed associations of MRI measures (grey matter volume, white matter hyperintensity volume, mean diffusivity, fractional anisotropy) with SLV. Regional distribution of associations was assessed by sparse partial least squares analyses. Higher SLV (mean: 8.4, SD: 3.3) was significantly associated with older age, slower gait speed, and poorer executive function and also with lower grey matter integrity measured by mean diffusivity (standardized beta=0.16; p=0.02). Associations between SLV and grey matter integrity were strongest for the hippocampus and anterior cingulate gyrus (both β=0.18) as compared to other regions. Associations of SLV with other neuroimaging markers were not significant. Lower integrity of normal-appearing grey matter may underlie higher SLV in older adults. Our results highlighted the hippocampus and anterior cingulate gyrus, regions involved in memory and executive function. These findings support previous research indicating a role for cognitive function in motor control. Higher SLV may indicate focal neuropathology in those without diagnosed neurologic disease.
PMCID: PMC4071448  PMID: 24792638
gait disorders; diffusion tensor imaging; aging; brain
21.  Genome-wide association study meta-analysis of chronic widespread pain: evidence for involvement of the 5p15.2 region 
Annals of the Rheumatic Diseases  2012;72(3):427-436.
Background and objectives
Chronic widespread pain (CWP) is a common disorder affecting ∼10% of the general population and has an estimated heritability of 48–52%. In the first large-scale genome-wide association study (GWAS) meta-analysis, we aimed to identify common genetic variants associated with CWP.
We conducted a GWAS meta-analysis in 1308 female CWP cases and 5791 controls of European descent, and replicated the effects of the genetic variants with suggestive evidence for association in 1480 CWP cases and 7989 controls. Subsequently, we studied gene expression levels of the nearest genes in two chronic inflammatory pain mouse models, and examined 92 genetic variants previously described associated with pain.
The minor C-allele of rs13361160 on chromosome 5p15.2, located upstream of chaperonin-containing-TCP1-complex-5 gene (CCT5) and downstream of FAM173B, was found to be associated with a 30% higher risk of CWP (minor allele frequency=43%; OR=1.30, 95% CI 1.19 to 1.42, p=1.2×10−8). Combined with the replication, we observed a slightly attenuated OR of 1.17 (95% CI 1.10 to 1.24, p=4.7×10−7) with moderate heterogeneity (I2=28.4%). However, in a sensitivity analysis that only allowed studies with joint-specific pain, the combined association was genome-wide significant (OR=1.23, 95% CI 1.14 to 1.32, p=3.4×10−8, I2=0%). Expression levels of Cct5 and Fam173b in mice with inflammatory pain were higher in the lumbar spinal cord, not in the lumbar dorsal root ganglions, compared to mice without pain. None of the 92 genetic variants previously described were significantly associated with pain (p>7.7×10−4).
We identified a common genetic variant on chromosome 5p15.2 associated with joint-specific CWP in humans. This work suggests that CCT5 and FAM173B are promising targets in the regulation of pain.
PMCID: PMC3691951  PMID: 22956598
Gene Polymorphism; Fibromyalgis/Pain Syndromes; Epidemiology
22.  Parent-of-origin specific allelic associations among 106 genomic loci for age at menarche 
Perry, John RB | Day, Felix | Elks, Cathy E | Sulem, Patrick | Thompson, Deborah J | Ferreira, Teresa | He, Chunyan | Chasman, Daniel I | Esko, Tõnu | Thorleifsson, Gudmar | Albrecht, Eva | Ang, Wei Q | Corre, Tanguy | Cousminer, Diana L | Feenstra, Bjarke | Franceschini, Nora | Ganna, Andrea | Johnson, Andrew D | Kjellqvist, Sanela | Lunetta, Kathryn L | McMahon, George | Nolte, Ilja M | Paternoster, Lavinia | Porcu, Eleonora | Smith, Albert V | Stolk, Lisette | Teumer, Alexander | Tšernikova, Natalia | Tikkanen, Emmi | Ulivi, Sheila | Wagner, Erin K | Amin, Najaf | Bierut, Laura J | Byrne, Enda M | Hottenga, Jouke-Jan | Koller, Daniel L | Mangino, Massimo | Pers, Tune H | Yerges-Armstrong, Laura M | Zhao, Jing Hua | Andrulis, Irene L | Anton-Culver, Hoda | Atsma, Femke | Bandinelli, Stefania | Beckmann, Matthias W | Benitez, Javier | Blomqvist, Carl | Bojesen, Stig E | Bolla, Manjeet K | Bonanni, Bernardo | Brauch, Hiltrud | Brenner, Hermann | Buring, Julie E | Chang-Claude, Jenny | Chanock, Stephen | Chen, Jinhui | Chenevix-Trench, Georgia | Collée, J. Margriet | Couch, Fergus J | Couper, David | Coveillo, Andrea D | Cox, Angela | Czene, Kamila | D’adamo, Adamo Pio | Smith, George Davey | De Vivo, Immaculata | Demerath, Ellen W | Dennis, Joe | Devilee, Peter | Dieffenbach, Aida K | Dunning, Alison M | Eiriksdottir, Gudny | Eriksson, Johan G | Fasching, Peter A | Ferrucci, Luigi | Flesch-Janys, Dieter | Flyger, Henrik | Foroud, Tatiana | Franke, Lude | Garcia, Melissa E | García-Closas, Montserrat | Geller, Frank | de Geus, Eco EJ | Giles, Graham G | Gudbjartsson, Daniel F | Gudnason, Vilmundur | Guénel, Pascal | Guo, Suiqun | Hall, Per | Hamann, Ute | Haring, Robin | Hartman, Catharina A | Heath, Andrew C | Hofman, Albert | Hooning, Maartje J | Hopper, John L | Hu, Frank B | Hunter, David J | Karasik, David | Kiel, Douglas P | Knight, Julia A | Kosma, Veli-Matti | Kutalik, Zoltan | Lai, Sandra | Lambrechts, Diether | Lindblom, Annika | Mägi, Reedik | Magnusson, Patrik K | Mannermaa, Arto | Martin, Nicholas G | Masson, Gisli | McArdle, Patrick F | McArdle, Wendy L | Melbye, Mads | Michailidou, Kyriaki | Mihailov, Evelin | Milani, Lili | Milne, Roger L | Nevanlinna, Heli | Neven, Patrick | Nohr, Ellen A | Oldehinkel, Albertine J | Oostra, Ben A | Palotie, Aarno | Peacock, Munro | Pedersen, Nancy L | Peterlongo, Paolo | Peto, Julian | Pharoah, Paul DP | Postma, Dirkje S | Pouta, Anneli | Pylkäs, Katri | Radice, Paolo | Ring, Susan | Rivadeneira, Fernando | Robino, Antonietta | Rose, Lynda M | Rudolph, Anja | Salomaa, Veikko | Sanna, Serena | Schlessinger, David | Schmidt, Marjanka K | Southey, Mellissa C | Sovio, Ulla | Stampfer, Meir J | Stöckl, Doris | Storniolo, Anna M | Timpson, Nicholas J | Tyrer, Jonathan | Visser, Jenny A | Vollenweider, Peter | Völzke, Henry | Waeber, Gerard | Waldenberger, Melanie | Wallaschofski, Henri | Wang, Qin | Willemsen, Gonneke | Winqvist, Robert | Wolffenbuttel, Bruce HR | Wright, Margaret J | Boomsma, Dorret I | Econs, Michael J | Khaw, Kay-Tee | Loos, Ruth JF | McCarthy, Mark I | Montgomery, Grant W | Rice, John P | Streeten, Elizabeth A | Thorsteinsdottir, Unnur | van Duijn, Cornelia M | Alizadeh, Behrooz Z | Bergmann, Sven | Boerwinkle, Eric | Boyd, Heather A | Crisponi, Laura | Gasparini, Paolo | Gieger, Christian | Harris, Tamara B | Ingelsson, Erik | Järvelin, Marjo-Riitta | Kraft, Peter | Lawlor, Debbie | Metspalu, Andres | Pennell, Craig E | Ridker, Paul M | Snieder, Harold | Sørensen, Thorkild IA | Spector, Tim D | Strachan, David P | Uitterlinden, André G | Wareham, Nicholas J | Widen, Elisabeth | Zygmunt, Marek | Murray, Anna | Easton, Douglas F | Stefansson, Kari | Murabito, Joanne M | Ong, Ken K
Nature  2014;514(7520):92-97.
Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality1. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation2,3, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P<5×10−8) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1/WDR25, MKRN3/MAGEL2 and KCNK9) demonstrating parent-of-origin specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and gamma-aminobutyric acid-B2 receptor signaling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.
PMCID: PMC4185210  PMID: 25231870
23.  Genome-wide association study identifies common loci influencing circulating glycated hemoglobin (HbA1c) levels in non-diabetic subjects: the Long Life Family Study (LLFS) 
Glycated hemoglobin (HbA1c) is a stable index of chronic glycemic status and hyperglycemia associated with progressive development of insulin resistance and frank diabetes. It is also associated with premature aging and increased mortality. To uncover novel loci for HbA1c that are associated with healthy aging, we conducted a genome-wide association study (GWAS) using non-diabetic participants in the Long Life Family Study (LLFS), a study with familial clustering of exceptional longevity in the US and Denmark.
A total of 4,088 non-diabetic subjects from the LLFS were used for GWAS discoveries, and a total of 8,231 non-diabetic subjects from the Atherosclerosis Risk in Communities Study (ARIC, in the MAGIC Consortium) and the Health, Aging, and Body Composition Study (HABC) were used for GWAS replications. HbA1c was adjusted for age, sex, centers, 20 principal components, without and with BMI. A linear mixed effects model was used for association testing.
Two known loci at GCK rs730497 (or rs2908282) and HK1 rs17476364 were confirmed (p < 5e–8). Of 25 suggestive (5e–8 < p < 1e–5) loci, one known (G6PC2 rs560887, replication p = 5e–5) and one novel (OR10R3P/SPTA1- rs12041363, replication p = 1e–17) loci were replicated (p < 0.0019). Similar findings resulted when HbA1c was further adjusted for BMI. Further validations are crucial for the remaining suggestive loci including the emerged variant near OR10R3P/SPTA1.
The analysis reconfirmed two known GWAS loci (GCK, HK1) and identified 25 suggestive loci including one reconfirmed variant in G6PC2 and one replicated variant near OR10R3P/SPTA1. Future focused survey of sequence elements containing mainly functional and regulatory variants may yield additional findings.
PMCID: PMC3965585  PMID: 24405752
Genome-wide association study; Non-enzymatic glycation; Glucose, insulin resistance and diabetes; Premature aging processes
24.  Relationship Between 25-Hydroxyvitamin D and Cognitive Function in Older Adults: The Health ABC Study 
To examine the relationship between 25-hydroxyvitamin D (25(OH)D) levels and cognitive performance over time in older adults in the Health, Aging, and Body Composition (Health ABC) study.
Prospective cohort study
Community-dwelling participants in Pittsburgh, PA, and Memphis, TN
2,777 well-functioning adults aged 70–79 at baseline with serum 25(OH)D measured at the 12 month follow-up visit and cognitive function measured at baseline and 4-year follow-up visit.
Vitamin D status was categorized as 25(OH)D levels <20 ng/mL, 20 - <30 ng/mL, or ≥ 30ng/mL. Cognition was measured using the Modified Mini-Mental State Exam (3MS) and Digit Symbol Substitution Test (DSST). Linear regression models adjusting for multiple covariates, including age, education, sex, race, site, season, physical activity, and comorbidities were used in the analysis.
Sixty-eight percent of participants had 25(OH)D levels<30 ng/mL. Lower 25(OH)D levels were associated with lower baseline cognitive scores on the 3MS (adjusted means (95% CI): 89.9 (89.4–90.4), 90.8 (90.4–91.3), and 90.6 (90.2–91.1) for <20, 20-<30, and ≥30ng/mL, respectively; p trend =0.02) and the DSST (35.2 (34.5–36.0), 35.9 (35.2–36.6), and 37.0 (36.3–37.8), p trend =0.01). Participants with low 25(OH)D levels had greater declines in 3MS scores over 4 years than those with higher levels (LS mean change (95% CI): −1.0 (−1.5 to −0.6), −0.8 (−1.2 to −0.3), and −0.2 (−0.7 to 0.2) for <20, 20-<30, and ≥30ng/mL, respectively; p=0.05). There was no significant difference in DSST decline by 25(OH)D level.
Low 25(OH)D levels were associated with worse global cognitive function and greater decline over time as measured by the 3MS. Intervention trials are needed to determine if vitamin D supplementation can reduce cognitive decline.
PMCID: PMC3989387  PMID: 24635412
Vitamin D; cognition; cognitive function; memory
25.  Novel Genetic Markers Associate with Atrial Fibrillation Risk in Europeans and Japanese 
To identify non-redundant atrial fibrillation (AF) genetic susceptibility signals and examine their cumulative relations with AF risk.
AF-associated loci span broad genomic regions that may contain multiple susceptibility signals. Whether multiple signals exist at AF loci has not been systematically explored.
We performed association testing conditioned on the most significant, independently associated genetic markers at nine established AF loci using two complementary techniques in 64,683 individuals of European ancestry (3,869 incident and 3,302 prevalent AF cases). Genetic risk scores were created and tested for association with AF in Europeans and an independent sample of 11,309 individuals of Japanese ancestry (7,916 prevalent AF cases).
We observed at least four distinct AF susceptibility signals on chromosome 4q25 upstream of PITX2, but not at the remaining eight AF loci. A multilocus score comprised of 12 genetic markers demonstrated an estimated 5-fold gradient in AF risk. We observed a similar spectrum of risk associated with these markers in Japanese. Regions containing AF signals on chromosome 4q25 displayed a greater degree of evolutionary conservation than the remainder of the locus, suggesting that they may tag regulatory elements.
The chromosome 4q25 AF locus is architecturally complex and harbors at least four AF susceptibility signals in individuals of European ancestry. Similar polygenic AF susceptibility exists between Europeans and Japanese. Future work is necessary to identify causal variants, determine mechanisms by which associated loci predispose to AF, and explore whether AF susceptibility signals classify individuals at risk for AF and related morbidity.
PMCID: PMC4009240  PMID: 24486271
Atrial fibrillation; atrial flutter; genetic; risk; prognosis

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