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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
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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
[show abstract]
[hide abstract]
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
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[show abstract]
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ABSTRACT: Recent progress in sequencing technologies makes it possible to identify rare and unique variants that may be associated with complex traits. However, the results of such efforts depend crucially on the use of efficient statistical methods and study designs. Although family-based designs might enrich a data set for familial rare disease variants, most existing rare variant association approaches assume independence of all individuals. We introduce here a framework for association testing of rare variants in family-based designs. This framework is an adaptation of the sequence kernel association test (SKAT) which allows us to control for family structure. Our adjusted SKAT (ASKAT) combines the SKAT approach and the factored spectrally transformed linear mixed models (FaST-LMMs) algorithm to capture family effects based on a LMM incorporating the realized proportion of the genome that is identical by descent between pairs of individuals, and using restricted maximum likelihood methods for estimation. In simulation studies, we evaluated type I error and power of this proposed method and we showed that regardless of the level of the trait heritability, our approach has good control of type I error and good power. Since our approach uses FaST-LMM to calculate variance components for the proposed mixed model, ASKAT is reasonably fast and can analyze hundreds of thousands of markers. Data from the UK twins consortium are presented to illustrate the ASKAT methodology.
Genetic Epidemiology 03/2013; · 3.44 Impact Factor
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Karani S Vimaleswaran,
Diane J Berry,
Chen Lu,
Emmi Tikkanen,
Stefan Pilz,
Linda T Hiraki,
Jason D Cooper,
Zari Dastani,
Rui Li,
Denise K Houston, [......],
Peter Kraft,
Cyrus Cooper,
Winfried März,
Chris Power,
Ruth J F Loos,
Thomas J Wang,
Marjo-Riitta Järvelin,
John C Whittaker,
Aroon D Hingorani,
Elina Hyppönen
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ABSTRACT: Obesity is associated with vitamin D deficiency, and both are areas of active public health concern. We explored the causality and direction of the relationship between body mass index (BMI) and 25-hydroxyvitamin D [25(OH)D] using genetic markers as instrumental variables (IVs) in bi-directional Mendelian randomization (MR) analysis.
We used information from 21 adult cohorts (up to 42,024 participants) with 12 BMI-related SNPs (combined in an allelic score) to produce an instrument for BMI and four SNPs associated with 25(OH)D (combined in two allelic scores, separately for genes encoding its synthesis or metabolism) as an instrument for vitamin D. Regression estimates for the IVs (allele scores) were generated within-study and pooled by meta-analysis to generate summary effects. Associations between vitamin D scores and BMI were confirmed in the Genetic Investigation of Anthropometric Traits (GIANT) consortium (n = 123,864). Each 1 kg/m(2) higher BMI was associated with 1.15% lower 25(OH)D (p = 6.52×10(-27)). The BMI allele score was associated both with BMI (p = 6.30×10(-62)) and 25(OH)D (-0.06% [95% CI -0.10 to -0.02], p = 0.004) in the cohorts that underwent meta-analysis. The two vitamin D allele scores were strongly associated with 25(OH)D (p≤8.07×10(-57) for both scores) but not with BMI (synthesis score, p = 0.88; metabolism score, p = 0.08) in the meta-analysis. A 10% higher genetically instrumented BMI was associated with 4.2% lower 25(OH)D concentrations (IV ratio: -4.2 [95% CI -7.1 to -1.3], p = 0.005). No association was seen for genetically instrumented 25(OH)D with BMI, a finding that was confirmed using data from the GIANT consortium (p≥0.57 for both vitamin D scores).
On the basis of a bi-directional genetic approach that limits confounding, our study suggests that a higher BMI leads to lower 25(OH)D, while any effects of lower 25(OH)D increasing BMI are likely to be small. Population level interventions to reduce BMI are expected to decrease the prevalence of vitamin D deficiency. Please see later in the article for the Editors' Summary.
PLoS Medicine 02/2013; 10(2):e1001383. · 16.27 Impact Factor
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Yi Lu,
Veronique Vitart,
Kathryn P Burdon,
Chiea Chuen Khor,
Yelena Bykhovskaya,
Alireza Mirshahi,
Alex W Hewitt,
Demelza Koehn,
Pirro G Hysi,
Wishal D Ramdas, [......],
Andrew J Lotery,
Christopher J Hammond,
Cornelia M van Duijn,
Michael A Hauser,
Yaron S Rabinowitz,
Norbert Pfeiffer,
David A Mackey,
Jamie E Craig,
Stuart Macgregor,
Tien Y Wong
[show abstract]
[hide abstract]
ABSTRACT: Central corneal thickness (CCT) is associated with eye conditions including keratoconus and glaucoma. We performed a meta-analysis on >20,000 individuals in European and Asian populations that identified 16 new loci associated with CCT at genome-wide significance (P < 5 × 10(-8)). We further showed that 2 CCT-associated loci, FOXO1 and FNDC3B, conferred relatively large risks for keratoconus in 2 cohorts with 874 cases and 6,085 controls (rs2721051 near FOXO1 had odds ratio (OR) = 1.62, 95% confidence interval (CI) = 1.4-1.88, P = 2.7 × 10(-10), and rs4894535 in FNDC3B had OR = 1.47, 95% CI = 1.29-1.68, P = 4.9 × 10(-9)). FNDC3B was also associated with primary open-angle glaucoma (P = 5.6 × 10(-4); tested in 3 cohorts with 2,979 cases and 7,399 controls). Further analyses implicate the collagen and extracellular matrix pathways in the regulation of CCT.
Nature Genetics 01/2013; · 35.53 Impact Factor
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Matthijs J H M van der Loos,
Cornelius A Rietveld,
Niina Eklund,
Philipp D Koellinger,
Fernando Rivadeneira,
Gonçalo R Abecasis,
Georgina A Ankra-Badu,
Sebastian E Baumeister,
Daniel J Benjamin,
Reiner Biffar, [......],
Henry Völzke,
H-Erich Wichmann,
Philipp S Wild,
Sara M Willems,
Gonneke Willemsen,
Frank J A van Rooij,
Patrick J F Groenen,
André G Uitterlinden,
Albert Hofman,
A Roy Thurik
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ABSTRACT: Economic variables such as income, education, and occupation are known to affect mortality and morbidity, such as cardiovascular disease, and have also been shown to be partly heritable. However, very little is known about which genes influence economic variables, although these genes may have both a direct and an indirect effect on health. We report results from the first large-scale collaboration that studies the molecular genetic architecture of an economic variable-entrepreneurship-that was operationalized using self-employment, a widely-available proxy. Our results suggest that common SNPs when considered jointly explain about half of the narrow-sense heritability of self-employment estimated in twin data (σg (2)/σP (2) = 25%, h (2) = 55%). However, a meta-analysis of genome-wide association studies across sixteen studies comprising 50,627 participants did not identify genome-wide significant SNPs. 58 SNPs with p<10(-5) were tested in a replication sample (n = 3,271), but none replicated. Furthermore, a gene-based test shows that none of the genes that were previously suggested in the literature to influence entrepreneurship reveal significant associations. Finally, SNP-based genetic scores that use results from the meta-analysis capture less than 0.2% of the variance in self-employment in an independent sample (p≥0.039). Our results are consistent with a highly polygenic molecular genetic architecture of self-employment, with many genetic variants of small effect. Although self-employment is a multi-faceted, heavily environmentally influenced, and biologically distal trait, our results are similar to those for other genetically complex and biologically more proximate outcomes, such as height, intelligence, personality, and several diseases.
PLoS ONE 01/2013; 8(4):e60542. · 4.09 Impact Factor
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Dana B Hancock,
María Soler Artigas,
Sina A Gharib,
Amanda Henry,
Ani Manichaikul,
Adaikalavan Ramasamy,
Daan W Loth,
Medea Imboden,
Beate Koch,
Wendy L McArdle, [......],
Vilmundur Gudnason,
H Marike Boezen,
R Graham Barr,
Patricia A Cassano,
David P Strachan,
Myriam Fornage,
Ian P Hall,
Josée Dupuis,
Martin D Tobin,
Stephanie J London
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ABSTRACT: Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV(1)), and its ratio to forced vital capacity (FEV(1)/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV(1) and FEV(1)/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest P(JMA = )5.00×10(-11)), HLA-DQB1 and HLA-DQA2 (smallest P(JMA = )4.35×10(-9)), and KCNJ2 and SOX9 (smallest P(JMA = )1.28×10(-8)) were associated with FEV(1)/FVC or FEV(1) in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects.
PLoS Genetics 12/2012; 8(12):e1003098. · 8.69 Impact Factor
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Brendan Keating,
Aruna T Bansal,
Susan Walsh,
Jonathan Millman,
Jonathan Newman,
Kenneth Kidd,
Bruce Budowle,
Arthur Eisenberg,
Joseph Donfack,
Paolo Gasparini, [......],
Hareesh Chandrupatla,
David L Duffy,
Scott D Gordon,
Pirro Hysi,
Fan Liu,
Sarah E Medland,
Laurence Rubin,
Nicholas G Martin, Timothy D Spector,
Manfred Kayser
[show abstract]
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ABSTRACT: When a forensic DNA sample cannot be associated directly with a previously genotyped reference sample by standard short tandem repeat profiling, the investigation required for identifying perpetrators, victims, or missing persons can be both costly and time consuming. Here, we describe the outcome of a collaborative study using the Identitas Version 1 (v1) Forensic Chip, the first commercially available all-in-one tool dedicated to the concept of developing intelligence leads based on DNA. The chip allows parallel interrogation of 201,173 genome-wide autosomal, X-chromosomal, Y-chromosomal, and mitochondrial single nucleotide polymorphisms for inference of biogeographic ancestry, appearance, relatedness, and sex. The first assessment of the chip's performance was carried out on 3,196 blinded DNA samples of varying quantities and qualities, covering a wide range of biogeographic origin and eye/hair coloration as well as variation in relatedness and sex. Overall, 95 % of the samples (N = 3,034) passed quality checks with an overall genotype call rate >90 % on variable numbers of available recorded trait information. Predictions of sex, direct match, and first to third degree relatedness were highly accurate. Chip-based predictions of biparental continental ancestry were on average ~94 % correct (further support provided by separately inferred patrilineal and matrilineal ancestry). Predictions of eye color were 85 % correct for brown and 70 % correct for blue eyes, and predictions of hair color were 72 % for brown, 63 % for blond, 58 % for black, and 48 % for red hair. From the 5 % of samples (N = 162) with <90 % call rate, 56 % yielded correct continental ancestry predictions while 7 % yielded sufficient genotypes to allow hair and eye color prediction. Our results demonstrate that the Identitas v1 Forensic Chip holds great promise for a wide range of applications including criminal investigations, missing person investigations, and for national security purposes.
Deutsche Zeitschrift für die Gesamte Gerichtliche Medizin 11/2012; · 2.59 Impact Factor
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ABSTRACT: Our aim in this longitudinal study was to evaluate to what extent fat and lean tissue mass variations are associated and can predict RKOA in a large sample of British women followed-up over 10 years. Kellgren/Lawrence (K/L), joint space narrowing (JSN) and osteophyte (OSP) grades were scored from radiographs of both knees in 909 middle-aged women from the Chingford registry. Body composition components were assessed using the dual energy X-ray absorptiometry (DXA) method. In cross-sectional analysis, combined effect of age, BMI and leg tissue composition was required for best fitting model explaining variations of K/L scoring and osteophytes at lateral compartment. To explain medial osteophytes, age and BMI were sufficient to generate the best fitting model. In prediction analysis, leg lean mass was the more powerful predictor of K/L, medial osteophytes than BMI. In conclusion, BMI appears to influence the development of knee OA through both fat and/or lean mass, depending on RKOA phenotype.
Archives of gerontology and geriatrics 10/2012; · 1.36 Impact Factor
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Massimo Mangino,
Shih-Jen Hwang, Timothy D Spector,
Steven C Hunt,
Masayuki Kimura,
Annette L Fitzpatrick,
Lene Christiansen,
Inge Petersen,
Clara C Elbers,
Tamara Harris, [......],
Fridtjof Thomas,
Elad Ziv,
Bruce M Psaty,
Joshua C Bis,
Jerome I Rotter,
Kent D Taylor,
Erin Smith,
Nicholas J Schork,
Daniel Levy,
Abraham Aviv
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ABSTRACT: Leukocyte telomere length (LTL) is associated with a number of common age-related diseases and is a heritable trait. Previous genome wide association studies (GWAS) identified two loci on chromosomes 3q26.2 (TERC) and 10q24.33 (OBFC1) that are associated with the inter-individual LTL variation. We performed a meta-analysis of 9,190 individuals from six independent GWAS and validated our findings in 2,226 individuals from four additional studies. We confirmed previously reported associations with OBFC1 (rs9419958 P=9.1x10(-11)) and with the telomerase RNA component TERC (rs1317082, P=1.1x10(-8)). We also identified two novel genomic regions associated with LTL variation that map near a conserved telomere maintenance complex component 1 (CTC1; rs3027234, P=3.6 × 10(-8)) on chromosome17p13.1 and zinc finger protein 676 (ZNF676; rs412658, P=3.3 × 10(-8)) on 19p12. The minor allele of rs3027234 was associated with both shorter LTL and lower expression of CTC1. Our findings are consistent with the recent observations that point mutations in CTC1 cause short telomeres in both Arabidopsis and humans affected by a rare Mendelian syndrome. Overall our results provide novel insights into the genetic architecture of inter-individual LTL variation in the general population.
Human Molecular Genetics 09/2012; · 7.64 Impact Factor
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Jie Huang,
Maria Sabater-Lleal,
Folkert W Asselbergs,
David Tregouet,
So-Youn Shin,
Jingzhong Ding,
Jens Baumert,
Tiphaine Oudot-Mellakh,
Lasse Folkersen,
Andrew D Johnson, [......],
Per Eriksson,
Francois Cambien,
Cardiogenics Consortium,
Pierre-Emmanuel Morange,
Wolfgang Koenig,
Nicole Soranzo,
Pim van der Harst,
Yongmei Liu,
Christopher J O'Donnell,
Anders Hamsten
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ABSTRACT: We conducted a genome-wide association study to identify novel associations between genetic variants and circulating plasminogen activator inhibitor-1 (PAI-1) concentration, and examined functional implications of variants and genes that were discovered. A discovery meta-analysis was performed in 19,599 subjects, followed by replication analysis of genome-wide significant (P<5x10(-8)) single nucleotide polymorphisms (SNPs) in 10,796 independent samples. We further examined associations with type 2 diabetes (T2D) and coronary artery disease (CAD), assessed the functional significance of the SNPs for gene expression in human tissues, and conducted RNA silencing experiments for one novel association. We confirmed the association of the 4G/5G proxy SNP rs2227631 in the promoter region of SERPINE1 (7q22.1) and discovered genome-wide significant associations at 3 additional loci: chromosome 7q22.1 close to SERPINE1 (rs6976053, discovery P=3.4x10(-10)); chromosome 11p15.2 within ARNTL (rs6486122, discovery P=3.0x10(-8)); and chromosome 3p25.2 within PPARG (rs11128603, discovery P=2.9x10(-8)). Replication was achieved for the 7q22.1 and 11p15.2 loci. There was nominal association with T2D and CAD at ARNTL (P<0.05). Functional studies identified MUC3 as a candidate gene for the second association signal on 7q22.1. In summary, SNPs in SERPINE1 and ARNTL, and a SNP associated with the expression of MUC3 were robustly associated with circulating levels of PAI-1.
Blood 09/2012; · 9.90 Impact Factor
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Katherine S Elliott,
Kay Chapman,
Aaron Day-Williams,
Kalliope Panoutsopoulou,
Lorraine Southam,
Cecilia M Lindgren,
Nigel Arden,
Nadim Aslam,
Fraser Birrell,
Ian Carluke, [......],
Andrew McCaskie,
William E R Ollier,
Ashok Rai,
Stuart Ralston,
Mike R Reed, Timothy D Spector,
Ana M Valdes,
Gillian A Wallis,
Mark Wilkinson,
Eleftheria Zeggini
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ABSTRACT: OBJECTIVES: Obesity as measured by body mass index (BMI) is one of the major risk factors for osteoarthritis. In addition, genetic overlap has been reported between osteoarthritis and normal adult height variation. We investigated whether this relationship is due to a shared genetic aetiology on a genome-wide scale. METHODS: We compared genetic association summary statistics (effect size, p value) for BMI and height from the GIANT consortium genome-wide association study (GWAS) with genetic association summary statistics from the arcOGEN consortium osteoarthritis GWAS. Significance was evaluated by permutation. Replication of osteoarthritis association of the highlighted signals was investigated in an independent dataset. Phenotypic information of height and BMI was accounted for in a separate analysis using osteoarthritis-free controls. RESULTS: We found significant overlap between osteoarthritis and height (p=3.3×10(-5) for signals with p≤0.05) when the GIANT and arcOGEN GWAS were compared. For signals with p≤0.001 we found 17 shared signals between osteoarthritis and height and four between osteoarthritis and BMI. However, only one of the height or BMI signals that had shown evidence of association with osteoarthritis in the arcOGEN GWAS was also associated with osteoarthritis in the independent dataset: rs12149832, within the FTO gene (combined p=2.3×10(-5)). As expected, this signal was attenuated when we adjusted for BMI. CONCLUSIONS: We found a significant excess of shared signals between both osteoarthritis and height and osteoarthritis and BMI, suggestive of a common genetic aetiology. However, only one signal showed association with osteoarthritis when followed up in a new dataset.
Annals of the rheumatic diseases 09/2012; · 8.11 Impact Factor
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Fan Liu,
Fedde Van Der Lijn,
Claudia Schurmann,
Gu Zhu,
M Mallar Chakravarty,
Pirro G Hysi,
Andreas Wollstein,
Oscar Lao,
Marleen De Bruijne,
M Arfan Ikram, [......],
Sarah E Medland,
Grant W Montgomery,
Margaret J Wright,
Carol Wicking,
Stefan Boehringer, Timothy D Spector,
Tomá Š Paus,
Nicholas G Martin,
Reiner Biffar,
Manfred Kayser
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ABSTRACT: Inter-individual variation in facial shape is one of the most noticeable phenotypes in humans, and it is clearly under genetic regulation; however, almost nothing is known about the genetic basis of normal human facial morphology. We therefore conducted a genome-wide association study for facial shape phenotypes in multiple discovery and replication cohorts, considering almost ten thousand individuals of European descent from several countries. Phenotyping of facial shape features was based on landmark data obtained from three-dimensional head magnetic resonance images (MRIs) and two-dimensional portrait images. We identified five independent genetic loci associated with different facial phenotypes,
suggesting the involvement of five candidate genes—PRDM16, PAX3, TP63, C5orf50, and COL17A1—in the determination of the human face. Three of them have been implicated previously in vertebrate craniofacial development and disease, and the remaining two genes potentially represent novel players in the molecular networks governing facial development. Our finding at PAX3 influencing the position of the nasion replicates a recent GWAS of facial features. In addition to the reported GWA findings, we established links between common DNA variants previously associated with NSCL/P at 2p21, 8q24, 13q31,
and 17q22 and normal facial-shape variations based on a candidate gene approach. Overall our study implies that DNA variants in genes essential for craniofacial development contribute with relatively small effect size to the spectrum of normal variation in human facial morphology. This observation has important consequences for future studies aiming to identify more genes involved in the human facial morphology, as well as for potential applications of DNA prediction of facial shape such as in future forensic applications.
PLoS Genetics 09/2012; · 8.69 Impact Factor
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Karin J H Verweij,
Anna A E Vinkhuyzen,
Beben Benyamin,
Michael T Lynskey,
Lydia Quaye,
Arpana Agrawal,
Scott D Gordon,
Grant W Montgomery,
Pamela A F Madden,
Andrew C Heath, Timothy D Spector,
Nicholas G Martin,
Sarah E Medland
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ABSTRACT: While initiation of cannabis use is around 40% heritable, not much is known about the underlying genetic aetiology. Here, we meta-analysed two genome-wide association studies of initiation of cannabis use with > 10 000 individuals. None of the genetic variants reached genome-wide significance. We also performed a gene-based association test, which also revealed no significant effects of individual genes. Finally, we estimated that only approximately 6% of the variation in cannabis initiation is due to common genetic variants. Future genetic studies using larger sample sizes and different methodologies (including sequencing) might provide more insight in the complex genetic aetiology of cannabis use.
Addiction Biology 07/2012; · 4.83 Impact Factor
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ABSTRACT: The association of FTO gene variants with body mass index (BMI) and other obesity characteristics is well established. However, uncertainties remain whether the association is present only in young populations and whether it is attributable to body fat mass specifically. We aimed to clarify these two questions in a large sample (N= 4,523 individuals) of middle-aged and older (range 40-80 years) British female twins. The women were assessed for BMI, waist and hip circumference, total lean (LBM) and fat (FBM) body mass. Since the majority of FTO association signals have been reported in a haploblock bordering 52,355-52,408 kb (on chromosome 16q12.2), we examined five genotyped and 43 imputed SNPs mapped to this block. Canonical correlation and other association analyses showed significant and consistent association between the selected SNP and studied body composition phenotypes, with p-values reaching p= 0.000004. Of particular interest, in addition to the expected significant associations between FTO variants and FBM, we also identified significant associations with LBM. These results suggest that the association between FTO variants and body composition phenotypes is present across a wide range of ages, and that FTO appears primarily to affect the amount of body soft tissue, influencing both fat and lean mass.
Annals of Human Genetics 07/2012; 76(5):333-41. · 2.57 Impact Factor
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ABSTRACT: Compared with younger people, older people are much more variable in their organ function, and these large individual differences contribute to the complexity of geriatric medicine. What determines this variability? Is it due to the accumulation of different life experiences, or because of the variation in the genes we are born with, or an interaction of both? This paper reviews key findings from ageing twin cohorts probing these questions. Twin studies are the perfect natural experiment to dissect out genes and life experiences. We discuss the paradox that ageing is strongly determined by heritable factors (an influence that often gets stronger with time), yet longevity and lifespan seem not to be so heritable. We then focus on the intriguing question of why DNA sequence-identical twins might age differently. Animal studies are increasingly showing that epigenetic modifications occurring in early development and adulthood, might be key to ageing phenomena but this is difficult to investigate longitudinally in human populations, due to ethical problems of intervention and long lifespan. We propose that identical twin studies using new and existing cohorts may be useful human models in which to investigate the interaction between the environment and genetics, mediated by epigenetic modifications.
Age and Ageing 07/2012; 41(5):581-6. · 3.09 Impact Factor
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Virginie J M Verhoeven,
Pirro G Hysi,
Seang-Mei Saw,
Veronique Vitart,
Alireza Mirshahi,
Jeremy A Guggenheim,
Mary Frances Cotch,
Kenji Yamashiro,
Paul N Baird,
David A Mackey, [......],
Sudha K Iyengar,
Paul Mitchell,
Jie Jin Wang,
René Höhn,
Norbert Pfeiffer,
Joan E Bailey-Wilson,
Dwight Stambolian,
Tien-Yin Wong,
Christopher J Hammond,
Caroline C W Klaver
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ABSTRACT: Myopia is a complex genetic disorder and a common cause of visual impairment among working age adults. Genome-wide association studies have identified susceptibility loci on chromosomes 15q14 and 15q25 in Caucasian populations of European ancestry. Here, we present a confirmation and meta-analysis study in which we assessed whether these two loci are also associated with myopia in other populations. The study population comprised 31 cohorts from the Consortium of Refractive Error and Myopia (CREAM) representing 4 different continents with 55,177 individuals; 42,845 Caucasians and 12,332 Asians. We performed a meta-analysis of 14 single nucleotide polymorphisms (SNPs) on 15q14 and 5 SNPs on 15q25 using linear regression analysis with spherical equivalent as a quantitative outcome, adjusted for age and sex. We calculated the odds ratio (OR) of myopia versus hyperopia for carriers of the top-SNP alleles using a fixed effects meta-analysis. At locus 15q14, all SNPs were significantly replicated, with the lowest P value 3.87 × 10(-12) for SNP rs634990 in Caucasians, and 9.65 × 10(-4) for rs8032019 in Asians. The overall meta-analysis provided P value 9.20 × 10(-23) for the top SNP rs634990. The risk of myopia versus hyperopia was OR 1.88 (95 % CI 1.64, 2.16, P < 0.001) for homozygous carriers of the risk allele at the top SNP rs634990, and OR 1.33 (95 % CI 1.19, 1.49, P < 0.001) for heterozygous carriers. SNPs at locus 15q25 did not replicate significantly (P value 5.81 × 10(-2) for top SNP rs939661). We conclude that common variants at chromosome 15q14 influence susceptibility for myopia in Caucasian and Asian populations world-wide.
Human Genetics 06/2012; 131(9):1467-80. · 5.07 Impact Factor
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ABSTRACT: The rate of bone loss varies across the aging period via multiple complex mechanisms. Therefore, the role of genetic factors on bone loss may also change similarly. In this study, we investigated the effect of age on the genetic component of bone loss in a large twin-based longitudinal study. During 17 years of follow-up in TwinsUK and Healthy Ageing Twin Study (HATS), 15,491 hip and lumbar spine dual-energy X-ray absorptiometry (DXA) scans were performed in 7056 twins. Out of these subjects, 2716 female twins aged >35 years with at least two scans separated for >4 years (mean follow-up 9.7 years) were included in this analysis. We used a mixed-effects random-coefficients regression model to predict hip and spine bone mineral density (BMD) values for exact ages of 40, 45, 50, 55, 60, 65, 70, 75, and 80 years, with adjustment for baseline age, weight, height, and duration of hormone replacement therapy. We then estimated heritability of the changes in BMD measures between these age ranges. Heritability estimates for cross-sectional hip and spine BMD were high (ranging between 69% and 88%) at different ages. Heritability of change of BMD was lower and more variable, generally ranging from 0% to 40% for hip and 0% to 70% for spine; between age 40 and 45 years genetic factors explained 39.9% (95% confidence interval [CI], 25%-53%) of variance of BMD loss for total hip, 46.4% (95% CI, 32%-58%) for femoral neck, and 69.5% (95% CI, 59%-77%) for lumbar spine. These estimates decreased with increasing age, and there appeared to be no heritability of BMD changes after the age of 65 years. There was some evidence at the spine for shared genetic effects between cross-sectional and longitudinal BMD. Whereas genetic factors appear to have an important role in bone loss in early postmenopausal women, nongenetic mechanisms become more important determinants of bone loss with advanced age. © 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 05/2012; 27(10):2170-8. · 6.04 Impact Factor
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Leopold Parts,
Åsa K Hedman,
Sarah Keildson,
Andrew J Knights,
Cei Abreu-Goodger,
Martijn van de Bunt,
José Afonso Guerra-Assunção,
Nenad Bartonicek,
Stijn van Dongen,
Reedik Mägi, [......],
Kerrin S Small,
Daniel Glass,
Anton J Enright,
John Winn,
Panos Deloukas,
Emmanouil T Dermitzakis,
Mark I McCarthy, Timothy D Spector,
Richard Durbin,
Cecilia M Lindgren
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ABSTRACT: Small RNAs are functional molecules that modulate mRNA transcripts and have been implicated in the aetiology of several common diseases. However, little is known about the extent of their variability within the human population. Here, we characterise the extent, causes, and effects of naturally occurring variation in expression and sequence of small RNAs from adipose tissue in relation to genotype, gene expression, and metabolic traits in the MuTHER reference cohort. We profiled the expression of 15 to 30 base pair RNA molecules in subcutaneous adipose tissue from 131 individuals using high-throughput sequencing, and quantified levels of 591 microRNAs and small nucleolar RNAs. We identified three genetic variants and three RNA editing events. Highly expressed small RNAs are more conserved within mammals than average, as are those with highly variable expression. We identified 14 genetic loci significantly associated with nearby small RNA expression levels, seven of which also regulate an mRNA transcript level in the same region. In addition, these loci are enriched for variants significant in genome-wide association studies for body mass index. Contrary to expectation, we found no evidence for negative correlation between expression level of a microRNA and its target mRNAs. Trunk fat mass, body mass index, and fasting insulin were associated with more than twenty small RNA expression levels each, while fasting glucose had no significant associations. This study highlights the similar genetic complexity and shared genetic control of small RNA and mRNA transcripts, and gives a quantitative picture of small RNA expression variation in the human population.
PLoS Genetics 05/2012; 8(5):e1002704. · 8.69 Impact Factor
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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
