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Hou-Feng Zheng,
Emma L Duncan,
Laura M Yerges-Armstrong,
Joel Eriksson,
Ulrica Bergström,
Paul J Leo,
William D Leslie,
David Goltzman,
John Blangero,
David A Hanley,
Melanie A Carless,
Elizabeth A Streeten,
Mattias Lorentzon, Matthew A Brown,
Tim D Spector,
Ulrika Pettersson-Kymmer,
Claes Ohlsson,
Braxton D Mitchell,
J Brent Richards
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[hide abstract]
ABSTRACT: BACKGROUND: Forearm fractures affect 1.7 million individuals worldwide each year and most occur earlier in life than hip fractures. While the heritability of forearm bone mineral density (BMD) and fracture is high, their genetic determinants are largely unknown. AIM: To identify genetic variants associated with forearm BMD and forearm fractures. METHODS: BMD at distal radius, measured by dual-energy x-ray absorptiometry, was tested for association with common genetic variants. We conducted a meta-analysis of genome-wide association studies for BMD in 5866 subjects of European descent and then selected the variants for replication in 715 Mexican American samples. Gene-based association was carried out to supplement the single-nucleotide polymorphism (SNP) association test. We then tested the BMD-associated SNPs for association with forearm fracture in 2023 cases and 3740 controls. RESULTS: We found that five SNPs in the introns of MEF2C were associated with forearm BMD at a genome-wide significance level (p<5×10(-8)) in meta-analysis (lead SNP, rs11951031[T] -0.20 SDs per allele, p=9.01×10(-9)). The gene-based association test suggested an association between MEF2C and forearm BMD (p=0.003). The association between MEF2C variants and risk of fracture did not achieve statistical significance (SNP rs12521522[A]: OR=1.14 (95% CI 0.92 to 1.35), p=0.14). Meta-analysis also revealed two genome-wide suggestive loci at CTNNA2 and 6q23.2. CONCLUSIONS: These findings demonstrate that variants at MEF2C were associated with forearm BMD, implicating this gene in the determination of BMD at forearm.
Journal of Medical Genetics 04/2013; · 6.36 Impact Factor
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Hou-Feng Zheng,
Jon H Tobias,
Emma Duncan,
David M Evans,
Joel Eriksson,
Lavinia Paternoster,
Laura M Yerges-Armstrong,
Terho Lehtimäki,
Ulrica Bergström,
Mika Kähönen, [......],
Jeff Liu,
Tim Spector,
Braxton D Mitchell,
Elizabeth A Streeten,
Robert Brommage,
Ulrika Pettersson-Kymmer, Matthew A Brown,
Claes Ohlsson,
J Brent Richards,
Mattias Lorentzon
[show abstract]
[hide abstract]
ABSTRACT: We aimed to identify genetic variants associated with cortical bone thickness (CBT) and bone mineral density (BMD) by performing two separate genome-wide association study (GWAS) meta-analyses for CBT in 3 cohorts comprising 5,878 European subjects and for BMD in 5 cohorts comprising 5,672 individuals. We then assessed selected single-nucleotide polymorphisms (SNPs) for osteoporotic fracture in 2,023 cases and 3,740 controls. Association with CBT and forearm BMD was tested for ∼2.5 million SNPs in each cohort separately, and results were meta-analyzed using fixed effect meta-analysis. We identified a missense SNP (Thr>Ile; rs2707466) located in the WNT16 gene (7q31), associated with CBT (effect size of -0.11 standard deviations [SD] per C allele, P = 6.2 × 10(-9)). This SNP, as well as another nonsynonymous SNP rs2908004 (Gly>Arg), also had genome-wide significant association with forearm BMD (-0.14 SD per C allele, P = 2.3 × 10(-12), and -0.16 SD per G allele, P = 1.2 × 10(-15), respectively). Four genome-wide significant SNPs arising from BMD meta-analysis were tested for association with forearm fracture. SNP rs7776725 in FAM3C, a gene adjacent to WNT16, was associated with a genome-wide significant increased risk of forearm fracture (OR = 1.33, P = 7.3 × 10(-9)), with genome-wide suggestive signals from the two missense variants in WNT16 (rs2908004: OR = 1.22, P = 4.9 × 10(-6) and rs2707466: OR = 1.22, P = 7.2 × 10(-6)). We next generated a homozygous mouse with targeted disruption of Wnt16. Female Wnt16(-/-) mice had 27% (P<0.001) thinner cortical bones at the femur midshaft, and bone strength measures were reduced between 43%-61% (6.5 × 10(-13)<P<5.9 × 10(-4)) at both femur and tibia, compared with their wild-type littermates. Natural variation in humans and targeted disruption in mice demonstrate that WNT16 is an important determinant of CBT, BMD, bone strength, and risk of fracture.
PLoS Genetics 07/2012; 8(7):e1002745. · 8.69 Impact Factor
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Joshua C Bis,
Charles DeCarli,
Albert Vernon Smith,
Fedde van der Lijn,
Fabrice Crivello,
Myriam Fornage,
Stephanie Debette,
Joshua M Shulman,
Helena Schmidt,
Velandai Srikanth, [......],
W T Longstreth, Matthew A Brown,
David A Bennett,
Cornelia M van Duijn,
Thomas H Mosley,
Reinhold Schmidt,
Christophe Tzourio,
Lenore J Launer,
M Arfan Ikram,
Sudha Seshadri
[show abstract]
[hide abstract]
ABSTRACT: Aging is associated with reductions in hippocampal volume that are accelerated by Alzheimer's disease and vascular risk factors. Our genome-wide association study (GWAS) of dementia-free persons (n = 9,232) identified 46 SNPs at four loci with P values of <4.0 × 10(-7). In two additional samples (n = 2,318), associations were replicated at 12q14 within MSRB3-WIF1 (discovery and replication; rs17178006; P = 5.3 × 10(-11)) and at 12q24 near HRK-FBXW8 (rs7294919; P = 2.9 × 10(-11)). Remaining associations included one SNP at 2q24 within DPP4 (rs6741949; P = 2.9 × 10(-7)) and nine SNPs at 9p33 within ASTN2 (rs7852872; P = 1.0 × 10(-7)); along with the chromosome 12 associations, these loci were also associated with hippocampal volume (P < 0.05) in a third younger, more heterogeneous sample (n = 7,794). The SNP in ASTN2 also showed suggestive association with decline in cognition in a largely independent sample (n = 1,563). These associations implicate genes related to apoptosis (HRK), development (WIF1), oxidative stress (MSR3B), ubiquitination (FBXW8) and neuronal migration (ASTN2), as well as enzymes targeted by new diabetes medications (DPP4), indicating new genetic influences on hippocampal size and possibly the risk of cognitive decline and dementia.
Nature Genetics 04/2012; 44(5):545-51. · 35.53 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
[show abstract]
[hide abstract]
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
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Joshua C Bis,,
Charles DeCarli,,
Albert Vernon Smith,,
Fedde van der Lijn,,
Fabrice Crivello,,
Myriam Fornage,,
Stephanie Debette,,
Joshua M Shulman,,
Helena Schmidt,,
Velandai Srikanth,, [......],
W T Longstreth Jr,, Matthew A Brown,,
David A Bennett,,
Cornelia M van Duijn,,
Thomas H Mosley,,
Reinhold Schmidt,,
Christophe Tzourio,,
Lenore J Launer,,
M Arfan Ikram,
Sudha Seshadri
[show abstract]
[hide abstract]
ABSTRACT: Aging is associated with reductions in hippocampal volume that are accelerated by Alzheimer's disease and vascular risk factors. Our genome-wide association study (GWAS) of dementia-free persons (n = 9,232) identified 46 SNPs at four loci with P values of <4.0 × 10 −7 . In two additional samples (n = 2,318), associations were replicated at 12q14 within MSRB3-WIF1 (discovery and replication; rs17178006; P = 5.3 × 10 −11) and at 12q24 near HRK-FBXW8 (rs7294919; P = 2.9 × 10 −11). Remaining associations included one SNP at 2q24 within DPP4 (rs6741949; P = 2.9 × 10 −7) and nine SNPs at 9p33 within ASTN2 (rs7852872; P = 1.0 × 10 −7); along with the chromosome 12 associations, these loci were also associated with hippocampal volume (P < 0.05) in a third younger, more heterogeneous sample (n = 7,794). The SNP in ASTN2 also showed suggestive association with decline in cognition in a largely independent sample (n = 1,563). These associations implicate genes related to apoptosis (HRK), development (WIF1), oxidative stress (MSR3B), ubiquitination (FBXW8) and neuronal migration (ASTN2), as well as enzymes targeted by new diabetes medications (DPP4), indicating new genetic influences on hippocampal size and possibly the risk of cognitive decline and dementia. Differences in hippocampal volume that appear with advancing age represent cumulative effects of early-life factors, life-course events and disease. Hippocampal atrophy is a recognized biological marker of Alzheimer's disease 1,2 ; however, it is influenced by various vascular and metabolic factors 3,4 . Because hippocampal volume is a heritable 5 , widely measurable trait that shows meaningful detectable changes throughout life, it is a suitable endophenotype for aging-related physio-logical processes and presymptomatic diseases, improving the power to detect genetic associations. We explored genetic influences on hippocampal volume by conduct-ing a cross-sectional genome-wide association analysis in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium 6 among 9,232 dementia-free persons from 8 community-based studies whose mean age ranged from 56 to 84 years (weighted average of 67.1 years). Each study imputed to a common set of SNPs from the Phase 2 HapMap Centre d'Etude du Polymorphisme Humain (CEPH) Utah residents of Northern and Western European ancestry (CEU) population using genotype data from Illumina or Affymetrix arrays; additive genetic models associating total hippocampal volume and genotype dosage were fitted with adjustment for age, sex and familial relationships (if applicable; Supplementary Note); and genomic control was applied. Study-specific results were combined in an inverse variance–weighted meta-analysis. We then conducted in silico replication of associations that reached genome-wide significance and sought additional evidence for sug-gestive associations in a second-stage targeted meta-analysis of 2,318 subjects from two community-based studies: the Three City Study and an independent sample from the third expansion of the Rotterdam Study. Characteristics of the discovery and replication samples are given (Supplementary Table 1). A Manhattan plot of −log 10 (P values) from the discovery analysis is shown (Fig. 1), where P values for 46 SNPs at 4 loci (Supplementary Table 2) surpassed our replication threshold of P < 4.0 × 10 −7 corres-ponding to 1 expected false positive. Of these, 18 SNPs at 2 loci sur-passed a genome-wide significance threshold of P < 5.0 × 10 −8 : the 12q14 locus, which included WIF1, LEMD3 and MSRB3, and the 12q24 locus, which included HRK and FBXW8. We found evidence of replication (P < 0.01) for both associations. The remaining sug-gestive associations included SNPs at 2q24 within DPP4 and at 9p33 within ASTN2, which had consistent directions of association in the discovery and replication phases but did not attain genome-wide sig-nificance in a combined analysis. Estimates for each stage are shown (Table 1). Discovery GWAS results for the region around each signal were annotated with recombination rates and known genes (Fig. 2), and study-specific findings are shown (Fig. 3).
Nature Genetics 01/2012; 44(5):545-551. · 35.53 Impact Factor
