M Carola Zillikens

Publications (72)1117.12 Total impact

• Article: Genome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake.

  Toshiko Tanaka, Julius S Ngwa, Frank Ja van Rooij, M Carola Zillikens, Mary K Wojczynski, Alexis C Frazier-Wood, Denise K Houston, Stavroula Kanoni, Rozenn N Lemaitre, Jian'an Luan, [......], Terho Lehtimäki, Ruth Jf Loos, Marju Orho-Melander, Jerome I Rotter, Nicholas J Wareham, Jacqueline Cm Witteman, Luigi Ferrucci, George Dedoussis, L Adrienne Cupples, Jennifer A Nettleton
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  ABSTRACT: BACKGROUND: Macronutrient intake varies substantially between individuals, and there is evidence that this variation is partly accounted for by genetic variants. OBJECTIVE: The objective of the study was to identify common genetic variants that are associated with macronutrient intake. DESIGN: We performed 2-stage genome-wide association (GWA) meta-analysis of macronutrient intake in populations of European descent. Macronutrients were assessed by using food-frequency questionnaires and analyzed as percentages of total energy consumption from total fat, protein, and carbohydrate. From the discovery GWA (n = 38,360), 35 independent loci associated with macronutrient intake at P < 5 × 10(-6) were identified and taken forward to replication in 3 additional cohorts (n = 33,533) from the DietGen Consortium. For one locus, fat mass obesity-associated protein (FTO), cohorts with Illumina MetaboChip genotype data (n = 7724) provided additional replication data. RESULTS: A variant in the chromosome 19 locus (rs838145) was associated with higher carbohydrate (β ± SE: 0.25 ± 0.04%; P = 1.68 × 10(-8)) and lower fat (β ± SE: -0.21 ± 0.04%; P = 1.57 × 10(-9)) consumption. A candidate gene in this region, fibroblast growth factor 21 (FGF21), encodes a fibroblast growth factor involved in glucose and lipid metabolism. The variants in this locus were associated with circulating FGF21 protein concentrations (P < 0.05) but not mRNA concentrations in blood or brain. The body mass index (BMI)-increasing allele of the FTO variant (rs1421085) was associated with higher protein intake (β ± SE: 0.10 ± 0.02%; P = 9.96 × 10(-10)), independent of BMI (after adjustment for BMI, β ± SE: 0.08 ± 0.02%; P = 3.15 × 10(-7)). CONCLUSION: Our results indicate that variants in genes involved in nutrient metabolism and obesity are associated with macronutrient consumption in humans. Trials related to this study were registered at clinicaltrials.gov as NCT00005131 (Atherosclerosis Risk in Communities), NCT00005133 (Cardiovascular Health Study), NCT00005136 (Family Heart Study), NCT00005121 (Framingham Heart Study), NCT00083369 (Genetic and Environmental Determinants of Triglycerides), NCT01331512 (InCHIANTI Study), and NCT00005487 (Multi-Ethnic Study of Atherosclerosis).
  American Journal of Clinical Nutrition 05/2013; · 6.67 Impact Factor
• Article: Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture.

  Sonja I Berndt, Stefan Gustafsson, Reedik Mägi, Andrea Ganna, Eleanor Wheeler, Mary F Feitosa, Anne E Justice, Keri L Monda, Damien C Croteau-Chonka, Felix R Day, [......], Joel N Hirschhorn, Cecilia M Lindgren, Andrew P Morris, David Meyre, André Scherag, Mark I McCarthy, Elizabeth K Speliotes, Kari E North, Ruth J F Loos, Erik Ingelsson
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  ABSTRACT: Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
  Nature Genetics 04/2013; · 35.53 Impact Factor
• Article: Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture

  Sonja I Berndt, Stefan Gustafsson, Reedik Magi, Andrea Ganna, Eleanor Wheeler, Mary F Feitosa, Anne E Justice, Keri L Monda, Damien C Croteau-Chonka, Felix R Day, [......], Joel N Hirschhorn, Cecilia M Lindgren, Andrew P Morris, David Meyre, Andre Scherag, Mark I McCarthy, Elizabeth K Speliotes, Kari E North, Ruth J F Loos, Erik Ingelsson
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  ABSTRACT: Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
  Nature Genetics 04/2013; · 35.53 Impact Factor
• Article: Association of Adiposity Genetic Variants With Menarche Timing in 92,105 Women of European Descent.

  Lindsay Fernández-Rhodes, Ellen W Demerath, Diana L Cousminer, Ran Tao, Jill G Dreyfus, Tõnu Esko, Albert V Smith, Vilmundur Gudnason, Tamara B Harris, Lenore Launer, [......], Lynda M Rose, Paul M Ridker, Charles Poole, Joel N Hirschhorn, Joanne M Murabito, Daniel I Chasman, Elisabeth Widen, Kari E North, Ken K Ong, Nora Franceschini
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  ABSTRACT: Obesity is of global health concern. There are well-described inverse relationships between female pubertal timing and obesity. Recent genome-wide association studies of age at menarche identified several obesity-related variants. Using data from the ReproGen Consortium, we employed meta-analytical techniques to estimate the associations of 95 a priori and recently identified obesity-related (body mass index (weight (kg)/height (m)(2)), waist circumference, and waist:hip ratio) single-nucleotide polymorphisms (SNPs) with age at menarche in 92,116 women of European descent from 38 studies (1970-2010), in order to estimate associations between genetic variants associated with central or overall adiposity and pubertal timing in girls. Investigators in each study performed a separate analysis of associations between the selected SNPs and age at menarche (ages 9-17 years) using linear regression models and adjusting for birth year, site (as appropriate), and population stratification. Heterogeneity of effect-measure estimates was investigated using meta-regression. Six novel associations of body mass index loci with age at menarche were identified, and 11 adiposity loci previously reported to be associated with age at menarche were confirmed, but none of the central adiposity variants individually showed significant associations. These findings suggest complex genetic relationships between menarche and overall obesity, and to a lesser extent central obesity, in normal processes of growth and development.
  American journal of epidemiology 04/2013; · 5.59 Impact Factor
• Article: Higher Magnesium Intake Is Associated with Lower Fasting Glucose and Insulin, with No Evidence of Interaction with Select Genetic Loci, in a Meta-Analysis of 15 CHARGE Consortium Studies.

  Adela Hruby, Julius S Ngwa, Frida Renström, Mary K Wojczynski, Andrea Ganna, Göran Hallmans, Denise K Houston, Paul F Jacques, Stavroula Kanoni, Terho Lehtimäki, [......], Stephen B Kritchevsky, Marju Orho-Melander, Inga Prokopenko, Jerome I Rotter, David S Siscovick, Jacqueline C M Witteman, Paul W Franks, James B Meigs, Nicola M McKeown, Jennifer A Nettleton
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  ABSTRACT: Favorable associations between magnesium intake and glycemic traits, such as fasting glucose and insulin, are observed in observational and clinical studies, but whether genetic variation affects these associations is largely unknown. We hypothesized that single nucleotide polymorphisms (SNPs) associated with either glycemic traits or magnesium metabolism affect the association between magnesium intake and fasting glucose and insulin. Fifteen studies from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium provided data from up to 52,684 participants of European descent without known diabetes. In fixed-effects meta-analyses, we quantified 1) cross-sectional associations of dietary magnesium intake with fasting glucose (mmol/L) and insulin (ln-pmol/L) and 2) interactions between magnesium intake and SNPs related to fasting glucose (16 SNPs), insulin (2 SNPs), or magnesium (8 SNPs) on fasting glucose and insulin. After adjustment for age, sex, energy intake, BMI, and behavioral risk factors, magnesium (per 50-mg/d increment) was inversely associated with fasting glucose [β = -0.009 mmol/L (95% CI: -0.013, -0.005), P < 0.0001] and insulin [-0.020 ln-pmol/L (95% CI: -0.024, -0.017), P < 0.0001]. No magnesium-related SNP or interaction between any SNP and magnesium reached significance after correction for multiple testing. However, rs2274924 in magnesium transporter-encoding TRPM6 showed a nominal association (uncorrected P = 0.03) with glucose, and rs11558471 in SLC30A8 and rs3740393 near CNNM2 showed a nominal interaction (uncorrected, both P = 0.02) with magnesium on glucose. Consistent with other studies, a higher magnesium intake was associated with lower fasting glucose and insulin. Nominal evidence of TRPM6 influence and magnesium interaction with select loci suggests that further investigation is warranted.
  Journal of Nutrition 01/2013; · 3.92 Impact Factor
• Source

  Available from: Gabriëlle Buitendijk

  Article: High Bone Mineral Density and Fracture Risk in Type 2 Diabetes as Skeletal Complications of Inadequate Glucose Control: The Rotterdam Study.

  Ling Oei, M Carola Zillikens, Abbas Dehghan, Gabriëlle H S Buitendijk, Martha C Castaño-Betancourt, Karol Estrada, Lisette Stolk, Edwin H G Oei, Joyce B J van Meurs, Joseph A M J L Janssen, Albert Hofman, Johannes P T M van Leeuwen, Jacqueline C M Witteman, Huibert A P Pols, André G Uitterlinden, Caroline C W Klaver, Oscar H Franco, Fernando Rivadeneira
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  ABSTRACT: OBJECTIVE Individuals with type 2 diabetes have increased fracture risk despite higher bone mineral density (BMD). Our aim was to examine the influence of glucose control on skeletal complications.RESEARCH DESIGN AND METHODS Data of 4,135 participants of the Rotterdam Study, a prospective population-based cohort, were available (mean follow-up 12.2 years). At baseline, 420 participants with type 2 diabetes were classified by glucose control (according to HbA(1c) calculated from fructosamine), resulting in three comparison groups: adequately controlled diabetes (ACD; n = 203; HbA(1c) <7.5%), inadequately controlled diabetes (ICD; n = 217; HbA(1c) ≥7.5%), and no diabetes (n = 3,715). Models adjusted for sex, age, height, and weight (and femoral neck BMD) were used to test for differences in bone parameters and fracture risk (hazard ratio [HR] [95% CI]).RESULTSThe ICD group had 1.1-5.6% higher BMD, 4.6-5.6% thicker cortices, and -1.2 to -1.8% narrower femoral necks than ACD and ND, respectively. Participants with ICD had 47-62% higher fracture risk than individuals without diabetes (HR 1.47 [1.12-1.92]) and ACD (1.62 [1.09-2.40]); whereas those with ACD had a risk similar to those without diabetes (0.91 [0.67-1.23]).CONCLUSIONS Poor glycemic control in type 2 diabetes is associated with fracture risk, high BMD, and thicker femoral cortices in narrower bones. We postulate that fragility in apparently "strong" bones in ICD can result from microcrack accumulation and/or cortical porosity, reflecting impaired bone repair.
  Diabetes care 01/2013; · 8.09 Impact Factor
• Article: Meta-Analysis Investigating Associations Between Healthy Diet and Fasting Glucose and Insulin Levels and Modification by Loci Associated With Glucose Homeostasis in Data From 15 Cohorts.

  Jennifer A Nettleton, Marie-France Hivert, Rozenn N Lemaitre, Nicola M McKeown, Dariush Mozaffarian, Toshiko Tanaka, Mary K Wojczynski, Adela Hruby, Luc Djoussé, Julius S Ngwa, [......], Stephen B Kritchevsky, Marju Orho-Melander, James S Pankow, Terho Lehtimäki, Jacqueline C M Witteman, Erik Ingelsson, David S Siscovick, George Dedoussis, James B Meigs, Paul W Franks
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  ABSTRACT: Whether loci that influence fasting glucose (FG) and fasting insulin (FI) levels, as identified by genome-wide association studies, modify associations of diet with FG or FI is unknown. We utilized data from 15 US and European cohort studies comprising 51,289 persons without diabetes to test whether genotype and diet interact to influence FG or FI concentration. We constructed a diet score using study-specific quartile rankings for intakes of whole grains, fish, fruits, vegetables, and nuts/seeds (favorable) and red/processed meats, sweets, sugared beverages, and fried potatoes (unfavorable). We used linear regression within studies, followed by inverse-variance-weighted meta-analysis, to quantify 1) associations of diet score with FG and FI levels and 2) interactions of diet score with 16 FG-associated loci and 2 FI-associated loci. Diet score (per unit increase) was inversely associated with FG (β = -0.004 mmol/L, 95% confidence interval: -0.005, -0.003) and FI (β = -0.008 ln-pmol/L, 95% confidence interval: -0.009, -0.007) levels after adjustment for demographic factors, lifestyle, and body mass index. Genotype variation at the studied loci did not modify these associations. Healthier diets were associated with lower FG and FI concentrations regardless of genotype at previously replicated FG- and FI-associated loci. Studies focusing on genomic regions that do not yield highly statistically significant associations from main-effect genome-wide association studies may be more fruitful in identifying diet-gene interactions.
  American journal of epidemiology 12/2012; · 5.59 Impact Factor
• Article: Gain-of-Function Lipoprotein Lipase Variant rs13702 Modulates Lipid Traits through Disruption of a MicroRNA-410 Seed Site.

  Kris Richardson, Jennifer A Nettleton, Noemi Rotllan, Toshiko Tanaka, Caren E Smith, Chao-Qiang Lai, Laurence D Parnell, Yu-Chi Lee, Jari Lahti, Rozenn N Lemaitre, [......], Jacqueline C M Witteman, Mark O Goodarzi, Terho Lehtimäki, Yongmei Liu, M Carola Zillikens, Yii-Der I Chen, André G Uitterlinden, Jerome I Rotter, Carlos Fernandez-Hernando, Jose M Ordovas
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  ABSTRACT: Genome-wide association studies (GWAS) have identified hundreds of genetic variants that are associated with lipid phenotypes. However, data supporting a functional role for these variants in the context of lipid metabolism are scarce. We investigated the association of the lipoprotein lipase (LPL) variant rs13702 with plasma lipids and explored its potential for functionality. The rs13702 minor allele had been predicted to disrupt a microRNA (miR) recognition element (MRE) seed site (MRESS) for the human microRNA-410 (miR-410). Furthermore, rs13702 is in linkage disequilibrium (LD) with several SNPs identified by GWAS. We performed a meta-analysis across ten cohorts of participants that showed a statistically significant association of rs13702 with triacylglycerols (TAG) (p = 3.18 × 10(-42)) and high-density lipoprotein cholesterol (HDL-C) (p = 1.35 × 10(-32)) with each copy of the minor allele associated with 0.060 mmol/l lower TAG and 0.041 mmol/l higher HDL-C. Our data showed that an LPL 3' UTR luciferase reporter carrying the rs13702 major T allele was reduced by 40% in response to a miR-410 mimic. We also evaluated the interaction between intake of dietary fatty acids and rs13702. Meta-analysis demonstrated a significant interaction between rs13702 and dietary polyunsaturated fatty acid (PUFA) with respect to TAG concentrations (p = 0.00153), with the magnitude of the inverse association between dietary PUFA intake and TAG concentration showing -0.007 mmol/l greater reduction. Our results suggest that rs13702 induces the allele-specific regulation of LPL by miR-410 in humans. This work provides biological and potential clinical relevance for previously reported GWAS variants associated with plasma lipid phenotypes.
  The American Journal of Human Genetics 12/2012; · 10.60 Impact Factor
• Article: FTO genotype is associated with phenotypic variability of body mass index.

  Jian Yang, Ruth J F Loos, Joseph E Powell, Sarah E Medland, Elizabeth K Speliotes, Daniel I Chasman, Lynda M Rose, Gudmar Thorleifsson, Valgerdur Steinthorsdottir, Reedik Mägi, [......], David P Strachan, William G Hill, Harold Snieder, Paul M Ridker, Unnur Thorsteinsdottir, Kari Stefansson, Timothy M Frayling, Joel N Hirschhorn, Michael E Goddard, Peter M Visscher
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  ABSTRACT: There is evidence across several species for genetic control of phenotypic variation of complex traits, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using ∼170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype), is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of ∼0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI, possibly mediated by DNA methylation. Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.
  Nature 09/2012; 490(7419):267-72. · 36.28 Impact Factor
• Article: Review of radiological scoring methods of osteoporotic vertebral fractures for clinical and research settings.

  Ling Oei, Fernando Rivadeneira, Felisia Ly, Stephan J Breda, M Carola Zillikens, Albert Hofman, André G Uitterlinden, Gabriel P Krestin, Edwin H G Oei
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  ABSTRACT: BACKGROUND: Osteoporosis is the most common metabolic bone disease; vertebral fractures are the most common osteoporotic fractures. METHODS: Several radiological scoring methods using different criteria for osteoporotic vertebral fractures exist. Quantitative morphometry (QM) uses ratios derived from direct vertebral body height measurements to define fractures. Semi-quantitative (SQ) visual grading is performed according to height and area reduction. The algorithm-based qualitative (ABQ) method introduced a scheme to systematically rule out non-fracture deformities and diagnoses osteoporotic vertebral fractures based on endplate depression. The concordance across methods is currently a matter of debate. RESULTS: This article reviews the most commonly applied standardised radiographic scoring methods for osteoporotic vertebral fractures, attaining an impartial perspective of benefits and limitations. It provides image examples and discusses aspects that facilitate large-scale application, such as automated image analysis software and different imaging investigations. It also reviews the implications of different fracture definitions for scientific research and clinical practice. CONCLUSION: Accurate standardised scoring methods for assessing osteoporotic vertebral fractures are crucial, considering that differences in definition will have implications for patient care and scientific research. Evaluation of the feasibility and concordance among methods will allow establishing their benefits and limitations, and most importantly, optimise their effectiveness for widespread application. KEY POINTS : • Several scoring methods using different criteria for assessing osteoporotic vertebral fractures exist. • Standardised osteoporotic vertebral fracture assessment should be applicable to different radiological investigations. • Accurate assessment of osteoporotic vertebral fractures is essential for proper patient management. • Optimising feasibility of scoring methods enables widespread use in scientific research. • Assessment of concordance between methods is important for application in patient care.
  European Radiology 08/2012; · 3.22 Impact Factor
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  Available from: Sjur Reppe

  Article: Meta-analysis of genome-wide scans for total body BMD in children and adults reveals allelic heterogeneity and age-specific effects at the WNT16 locus.

  Carolina Medina-Gomez, John P Kemp, Karol Estrada, Joel Eriksson, Jeff Liu, Sjur Reppe, David M Evans, Denise H M Heppe, Liesbeth Vandenput, Lizbeth Herrera, [......], Albert Hofman, Vincent W V Jaddoe, George Davey Smith, Mattias Lorentzon, Kaare M Gautvik, André G Uitterlinden, Robert Brommage, Claes Ohlsson, Jonathan H Tobias, Fernando Rivadeneira
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  ABSTRACT: To identify genetic loci influencing bone accrual, we performed a genome-wide association scan for total-body bone mineral density (TB-BMD) variation in 2,660 children of different ethnicities. We discovered variants in 7q31.31 associated with BMD measurements, with the lowest P = 4.1 × 10(-11) observed for rs917727 with minor allele frequency of 0.37. We sought replication for all SNPs located ± 500 kb from rs917727 in 11,052 additional individuals from five independent studies including children and adults, together with de novo genotyping of rs3801387 (in perfect linkage disequilibrium (LD) with rs917727) in 1,014 mothers of children from the discovery cohort. The top signal mapping in the surroundings of WNT16 was replicated across studies with a meta-analysis P = 2.6 × 10(-31) and an effect size explaining between 0.6%-1.8% of TB-BMD variance. Conditional analyses on this signal revealed a secondary signal for total body BMD (P = 1.42 × 10(-10)) for rs4609139 and mapping to C7orf58. We also examined the genomic region for association with skull BMD to test if the associations were independent of skeletal loading. We identified two signals influencing skull BMD variation, including rs917727 (P = 1.9 × 10(-16)) and rs7801723 (P = 8.9 × 10(-28)), also mapping to C7orf58 (r(2) = 0.50 with rs4609139). Wnt16 knockout (KO) mice with reduced total body BMD and gene expression profiles in human bone biopsies support a role of C7orf58 and WNT16 on the BMD phenotypes observed at the human population level. In summary, we detected two independent signals influencing total body and skull BMD variation in children and adults, thus demonstrating the presence of allelic heterogeneity at the WNT16 locus. One of the skull BMD signals mapping to C7orf58 is mostly driven by children, suggesting temporal determination on peak bone mass acquisition. Our life-course approach postulates that these genetic effects influencing peak bone mass accrual may impact the risk of osteoporosis later in life.
  PLoS Genetics 07/2012; 8(7):e1002718. · 8.69 Impact Factor
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  Available from: José M Olmos

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

  Ching-Ti Liu, Karol Estrada, Laura M Yerges-Armstrong, Najaf Amin, Evangelos Evangelou, Guo Li, Ryan L Minster, Melanie A Carless, Candace M Kammerer, Ling Oei, [......], Bruce M Psaty, John A Robbins, M Carola Zillikens, Cornelia M Vanduijn, Richard L Prince, David Karasik, Fernando Rivadeneira, Douglas P Kiel, L Adrienne Cupples, Yi-Hsiang Hsu
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  ABSTRACT: 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.
  Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 06/2012; 27(10):2051-64. · 6.04 Impact Factor
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  Available from: Johannes van Leeuwen

  Article: The Role of Body Mass Index, Insulin, and Adiponectin in the Relation Between Fat Distribution and Bone Mineral Density

  M. Carola Zillikens, André G. Uitterlinden, Johannes P. T. M. van Leeuwen, Anne L. Berends, Peter Henneman, Ko Willems van Dijk, Ben A. Oostra, Cornelia M. van Duijn, Huibert A. P. Pols, Fernando Rivadeneira
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  ABSTRACT: Despite the positive association between body mass index (BMI) and bone mineral density (BMD) and content (BMC), the role of fat distribution in BMD/BMC remains unclear. We examined relationships between BMD/BMC and various measurements of fat distribution and studied the role of BMI, insulin, and adiponectin in these relations. Using a cross-sectional investigation of 2631 participants from the Erasmus Rucphen Family study, we studied associations between BMD (using dual-energy X-ray absorptiometry (DXA]) at the hip, lumbar spine, total body (BMD and BMC), and fat distribution by the waist-to-hip ratio (WHR), waist-to-thigh ratio (WTR), and DXA-based trunk-to-leg fat ratio and android-to-gynoid fat ratio. Analyses were stratified by gender and median age (48.0years in women and 49.2years in men) and were performed with and without adjustment for BMI, fasting insulin, and adiponectin. Using linear regression (adjusting for age, height, smoking, and use of alcohol), most relationships between fat distribution and BMD and BMC were positive, except for WTR. After BMI adjustment, most correlations were negative except for trunk-to-leg fat ratio in both genders. No consistent influence of age or menopausal status was found. Insulin and adiponectin levels did not explain either positive or negative associations. In conclusion, positive associations between android fat distribution and BMD/BMC are explained by higher BMI but not by higher insulin and/or lower adiponectin levels. Inverse associations after adjustment for BMI suggest that android fat deposition as measured by the WHR, WTR, and DXA-based android-to-gynoid fat ratio is not beneficial and possibly even deleterious for bone.
  Calcified Tissue International 04/2012; 86(2):116-125. · 2.38 Impact Factor
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  Available from: José M Olmos

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

  Karol Estrada, Unnur Styrkarsdottir, Evangelos Evangelou, Yi-Hsiang Hsu, Emma L Duncan, Evangelia E Ntzani, Ling Oei, Omar M E Albagha, Najaf Amin, John P Kemp, [......], Claes Ohlsson, David Karasik, J Brent Richards, Matthew A Brown, Kari Stefansson, André G Uitterlinden, Stuart H Ralston, John P A Ioannidis, Douglas P Kiel, Fernando Rivadeneira
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  ABSTRACT: 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.
  Nature Genetics 04/2012; 44(5):491-501. · 35.53 Impact Factor
• Article: The association between waist circumference and risk of mortality considering body mass index in 65- to 74-year-olds: a meta-analysis of 29 cohorts involving more than 58 000 elderly persons.

  Ellen L de Hollander, Wanda Je Bemelmans, Hendriek C Boshuizen, Nele Friedrich, Henri Wallaschofski, Pilar Guallar-Castillón, Stefan Walter, M Carola Zillikens, Annika Rosengren, Lauren Lissner, Julie K Bassett, Graham G Giles, Nicola Orsini, Noor Heim, Marjolein Visser, Lisette Cpgm de Groot
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  ABSTRACT: For the elderly, the association between waist circumference (WC) and mortality considering body mass index (BMI) remains unclear, and thereby also the evidence base for using these anthropometric measures in clinical practice. This meta-analysis examined the association between WC categories and (cause-specific) mortality within BMI categories. Furthermore, the association of continuous WC with lowest and increased mortality risks was examined. Age- and smoking-adjusted relative risks (RRs) of mortality associated with WC-BMI categories and continuous WC (including WC and WC(2)) were calculated by the investigators and pooled by means of random-effects models. During a 5-year-follow-up of 32 678 men and 25 931 women, we ascertained 3318 and 1480 deaths, respectively. A large WC (men: ≥102 cm, women: ≥88 cm) was associated with increased all-cause mortality RRs for those in the 'healthy' weight {1.7 [95% confidence interval (CI): 1.2-2.2], 1.7 (95% CI: 1.3-2.3)}, overweight [1.1(95% CI: 1.0-1.3), 1.4 (95%: 1.1-1.7)] and obese [1.1 (95% CI: 1.0-1.3), 1.6 (95% CI: 1.3-1.9)] BMI category compared with the 'healthy' weight (20-24.9 kg/m(2)) and a small WC (<94 cm, men; <80 cm, women) category. Underweight was associated with highest all-cause mortality RRs in men [2.2 (95% CI: 1.8-2.8)] and women [2.3 (95% CI: 1.8-3.1]. We found a J-shaped association for continuous WC with all-cause, cardiovascular (CVD) and cancer, and a U-shaped association with respiratory disease mortality (P < 0.05). An all-cause (CVD) mortality RR of 2.0 was associated with a WC of 132 cm (123 cm) in men and 116 cm (105 cm) in women. Our results showed increased mortality risks for elderly people with an increased WC-even across BMI categories- and for those who were classified as 'underweight' using BMI. The results provide a solid basis for re-evaluation of WC cut-points in ageing populations.
  International Journal of Epidemiology 03/2012; 41(3):805-17. · 6.41 Impact Factor
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  Available from: Sarah G Buxbaum

  Article: Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.

  Zari Dastani, Marie-France Hivert, Nicholas Timpson, John R B Perry, Xin Yuan, Robert A Scott, Peter Henneman, Iris M Heid, Jorge R Kizer, Leo-Pekka Lyytikäinen, [......], Eric E Schadt, David P Strachan, Muredach P Reilly, Nilesh J Samani, Heribert Schunkert, L Adrienne Cupples, Manjinder S Sandhu, Paul M Ridker, Daniel J Rader, Sekar Kathiresan
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  ABSTRACT: Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10(-3), n = 22,044), increased triglycerides (p = 2.6×10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8×10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10(-13), n = 96,748) and decreased BMI (p = 1.4×10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.
  PLoS Genetics 03/2012; 8(3):e1002607. · 8.69 Impact Factor
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  Available from: Jerome I Rotter

  Article: Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways

  Lisette Stolk, John R B Perry, Daniel I Chasman, Chunyan He, Massimo Mangino, Patrick Sulem, Maja Barbalic, Linda Broer, Enda M Byrne, Florian Ernst, [......], Elizabeth A Streeten, Unnur Thorsteinsdottir, Manuela Uda, G Uitterlinden, Cornelia M van Duijn, Henry, Anna Murray, Joanne M Murabito, Jenny A Visser, Kathryn L Lunetta
  Nature Genetics 01/2012; 44(3):260-268. · 35.53 Impact Factor
• Article: A genome-wide association search for type 2 diabetes genes in African Americans.

  Nicholette D Palmer, Caitrin W McDonough, Pamela J Hicks, Bong H Roh, Maria R Wing, S Sandy An, Jessica M Hester, Jessica N Cooke, Meredith A Bostrom, Megan E Rudock, [......], Angelo Scuteri, David Schlessinger, Manuela Uda, Aimo Ruokonen, Marjo-Riitta Jarvelin, Dawn M Waterworth, Peter Vollenweider, Leena Peltonen, Vincent Mooser, Robert Sladek
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  ABSTRACT: African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.
  PLoS ONE 01/2012; 7(1):e29202. · 4.09 Impact Factor
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  Available from: Diederick Grobbee

  Article: Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways.

  Lisette Stolk, John R B Perry, Daniel I Chasman, Chunyan He, Massimo Mangino, Patrick Sulem, Maja Barbalic, Linda Broer, Enda M Byrne, Florian Ernst, [......], Elizabeth A Streeten, Unnur Thorsteinsdottir, Manuela Uda, André G Uitterlinden, Cornelia M van Duijn, Henry Völzke, Anna Murray, Joanne M Murabito, Jenny A Visser, Kathryn L Lunetta
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  ABSTRACT: To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 × 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-κB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.
  Nature Genetics 01/2012; 44(3):260-8. · 35.53 Impact Factor
• Article: Hyponatremia and bone: an emerging relationship.

  Ewout J Hoorn, George Liamis, Robert Zietse, M Carola Zillikens
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  ABSTRACT: Hyponatremia is the most common electrolyte disorder and is mainly known for its neurological complications. New studies suggest previously unrecognized complications of hyponatremia, including falls, osteoporosis and fractures. Because these novel associations are mainly derived from epidemiological studies, it remains unclear whether hyponatremia has a direct effect on bone or whether it is a surrogate marker of another etiology. However, one animal and one in vitro study now show that hyponatremia can have direct effects on bone, mainly via activation of osteoclasts. The association between hyponatremia and fractures appears to be independent of osteoporosis (defined as low BMD). Also, data suggest that this association cannot be fully explained by the possibility that hyponatremia predisposes to falls. Hyponatremia, therefore, also has an effect on bone quality that is not captured by BMD. Here, the emerging relationship between hyponatremia and bone is reviewed, with special emphasis on possible mechanisms, unanswered questions and clinical implications.
  Nature Reviews Endocrinology 01/2012; 8(1):33-9. · 9.97 Impact Factor