Migraine-Associated Common Genetic Variants Confer Greater Risk of Posterior vs. Anterior Circulation Ischemic Stroke☆.

OBJECTIVE: To examine potential genetic relationships between migraine and the two distinct phenotypes posterior circulation ischemic stroke (PCiS) and anterior circulation ischemic stroke (ACiS), we generated migraine polygenic risk scores (PRSs) and compared these between PCiS and ACiS, and separately vs. non-stroke control subjects. METHODS: Acute ischemic stroke cases were classified as PCiS or ACiS based on lesion location on diffusion-weighted MRI. Exclusion criteria were lesions in both vascular territories or uncertain territory; supratentorial PCiS with ipsilateral fetal posterior cerebral artery; and cases with atrial fibrillation. We generated migraine PRS for three migraine phenotypes (any migraine; migraine without aura; migraine with aura) using publicly available GWAS data and compared mean PRSs separately for PCiS and ACiS vs. non-stroke control subjects, and between each stroke phenotype. RESULTS: Our primary analyses included 464 PCiS and 1079 ACiS patients with genetic European ancestry. Compared to non-stroke control subjects (n=15396), PRSs of any migraine were associated with increased risk of PCiS (p=0.01-0.03) and decreased risk of ACiS (p=0.010-0.039). Migraine without aura PRSs were significantly associated with PCiS (p=0.008-0.028), but not with ACiS. When comparing PCiS vs. ACiS directly, migraine PRSs were higher in PCiS vs. ACiS for any migraine (p=0.001-0.010) and migraine without aura (p=0.032-0.048). Migraine with aura PRS did not show a differential association in our analyses. CONCLUSIONS: Our results suggest a stronger genetic overlap between unspecified migraine and migraine without aura with PCiS compared to ACiS. Possible shared mechanisms include dysregulation of cerebral vessel endothelial function.

Risk factors for Toxoplasma gondii seropositivity in the Old Order Amish.

Toxoplasma gondii (T. gondii) is an important human disease-causing parasite. In the USA, T. gondii infects >10% of the population, accrues economic losses of US$3.6 billion/year, and ranks as the second leading culprit of foodborne illness-related fatalities. We assessed toxoplasmosis risk among the Old Order Amish, a mostly homogenous population with a high prevalence of T. gondii seropositivity, using a questionnaire focusing on food consumption/preparation behaviours and environmental risk factors. Analyses were conducted using multiple logistic regression. Consuming raw meat, rare meat, or unpasteurised cow or goat milk products was associated with increased odds of seropositivity (unadjusted Odds Ratios: 2.192, 1.613, and 1.718 , respectively). In separate models by sex, consuming raw meat, or consuming unpasteurised cow or goat milk products, was associated with increased odds of seropositivity among women; washing hands after touching meat with decreased odds of seropositivity among women (adjusted OR (AOR): 0.462); and cleaning cat litterbox with increased odds of seropositivity among men (AOR: 5.241). This is the first study to assess associations between behavioural and environmental risk factors and T. gondii seropositivity in a US population with high seroprevalence for T. gondii. Our study emphasises the importance of proper food safety behaviours to avoid the risk of infection.

Detailed phenotyping of posterior vs. anterior circulation ischemic stroke: a multi-center MRI study.

OBJECTIVE: Posterior circulation ischemic stroke (PCiS) constitutes 20-30% of ischemic stroke cases. Detailed information about differences between PCiS and anterior circulation ischemic stroke (ACiS) remains scarce. Such information might guide clinical decision making and prevention strategies. We studied risk factors and ischemic stroke subtypes in PCiS vs. ACiS and lesion location on magnetic resonance imaging (MRI) in PCiS. METHODS: Out of 3,301 MRIs from 12 sites in the National Institute of Neurological Disorders and Stroke (NINDS) Stroke Genetics Network (SiGN), we included 2,381 cases with acute DWI lesions. The definition of ACiS or PCiS was based on lesion location. We compared the groups using Chi-squared and logistic regression. RESULTS: PCiS occurred in 718 (30%) patients and ACiS in 1663 (70%). Diabetes and male sex were more common in PCiS vs. ACiS (diabetes 27% vs. 23%, p < 0.05; male sex 68% vs. 58%, p < 0.001). Both were independently associated with PCiS (diabetes, OR = 1.29; 95% CI 1.04-1.61; male sex, OR = 1.46; 95% CI 1.21-1.78). ACiS more commonly had large artery atherosclerosis (25% vs. 20%, p < 0.01) and cardioembolic mechanisms (17% vs. 11%, p < 0.001) compared to PCiS. Small artery occlusion was more common in PCiS vs. ACiS (20% vs. 14%, p < 0.001). Small artery occlusion accounted for 47% of solitary brainstem infarctions. CONCLUSION: Ischemic stroke subtypes differ between the two phenotypes. Diabetes and male sex have a stronger association with PCiS than ACiS. Definitive MRI-based PCiS diagnosis aids etiological investigation and contributes additional insights into specific risk factors and mechanisms of injury in PCiS.

Association of plasma nitrite levels with obesity and metabolic syndrome in the Old Order Amish.

OBJECTIVES: Plasma nitrite is a metabolite of nitric oxide and reflects endogenous nitric oxide synthase (NOS) activity. Although plasma nitrites were previously linked with obesity and metabolic syndrome (MetS), the direction of association remains inconsistent, possibly due to sample heterogeneity. In a relatively homogeneous population, we hypothesized that nitrite levels will be positively associated with overweight/obesity and MetS. METHODS: Fasting nitrite levels were measured in 116 Old Order Amish (78% women). We performed age-and-sex-adjusted ancovas to compare nitrite levels between three groups (a) overweight/obese(-)MetS(-), (b) overweight/obese(+)MetS(-) and (c) overweight/obese(+)MetS)(+). Multivariate linear regressions were conducted on nitrite associations with continuous metabolic variables, with successive adjustments for demographics, body mass index, C-reactive protein and neopterin. RESULTS: Nitrite levels were higher in the obese/overweight(+)MetS(+) group than in the other two groups (p < 0.001). Nitrites were positively associated with levels of triglycerides (p < 0.0001), total cholesterol (p = 0.048), high-density lipoprotein/cholesterol ratio (p < 0.0001) and fasting glucose (p < 0.0001), and negatively correlated with high-density lipoprotein-cholesterol (p < 0.0001). These associations were robust to adjustments for body mass index and inflammatory markers. CONCLUSION: Further investigation of the connection between obesity/MetS and plasma nitrite levels may lead to novel dietary and pharmacological approaches that ultimately may contribute to reducing the increasing burden of obesity, MetS and cardiovascular morbidity and mortality.

CPT1A methylation is associated with plasma adiponectin.

BACKGROUND AND AIMS: Adiponectin, an adipose-secreted protein that has been linked to insulin sensitivity, plasma lipids, and inflammatory patterns, is an established biomarker for metabolic health. Despite clinical relevance and high heritability, the determinants of plasma adiponectin levels remain poorly understood. METHODS AND RESULTS: We conducted the first epigenome-wide cross-sectional study of adiponectin levels using methylation data on 368,051 cytosine-phosphate-guanine (CpG) sites in CD4+ T-cells from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN, n = 991). We fit linear mixed models, adjusting for age, sex, study site, T-cell purity, and family. We have identified a positive association (regression coefficient ± SE = 0.01 ± 0.001, P = 3.4 × 10-13) between plasma adiponectin levels and methylation of a CpG site in CPT1A, a key player in fatty acid metabolism. The association was replicated (n = 474, P = 0.0009) in whole blood samples from the Amish participants of the Heredity and Phenotype Intervention (HAPI) Heart Study as well as White (n = 592, P = 0.0005) but not Black (n = 243, P = 0.18) participants of the Bogalusa Heart Study (BHS). The association remained significant upon adjusting for BMI and smoking in GOLDN and HAPI but not BHS. We also identified associations between methylation loci in RNF145 and UFM1 and plasma adiponectin in GOLDN and White BHS participants, although the association was not robust to adjustment for BMI or smoking. CONCLUSION: We have identified and replicated associations between several biologically plausible loci and plasma adiponectin. These findings support the importance of epigenetic processes in metabolic traits, laying the groundwork for future translational applications.

Prospective Evaluation of Genetic Variation in Platelet Endothelial Aggregation Receptor 1 Reveals Aspirin-Dependent Effects on Platelet Aggregation Pathways.

Genetic variation in the platelet endothelial aggregation receptor 1 (PEAR1) gene, most notably rs12041331, is implicated in altered on-aspirin platelet aggregation and increased cardiovascular event risk. We prospectively tested the effects of aspirin administration at commonly prescribed doses (81, 162, and 324 mg/day) on agonist-induced platelet aggregation by rs12041331 genotype in 67 healthy individuals. Prior to aspirin administration, rs12041331 minor allele carriers had significantly reduced adenosine diphosphate (ADP)-induced platelet aggregation compared with noncarriers (P = 0.03) but was not associated with other platelet pathways. In contrast, rs12041331 was significantly associated with on-aspirin platelet aggregation when collagen and epinephrine were used to stimulate platelet aggregation (P < 0.05 for all associations), but not ADP. The influence of PEAR1 rs12041331 on platelet aggregation is pathway-specific and is altered by aspirin at therapeutic doses, but not in a dose-dependent manner. Additional studies are needed to determine the impact of PEAR1 on cardiovascular events in aspirin-treated patients.

Heritability of young- and old-onset ischaemic stroke.

BACKGROUND AND PURPOSE: Although the genetic contribution to stroke risk is well known, it remains unclear if young-onset stroke has a stronger genetic contribution than old-onset stroke. This study aims to compare the heritability of ischaemic stroke risk between young and old, using common genetic variants from whole-genome array data in population-based samples. METHODS: This analysis included 4050 ischaemic stroke cases and 5765 controls from six study populations of European ancestry; 47% of cases were young-onset stroke (age < 55 years). To quantify the heritability for stroke risk in these unrelated individuals, the pairwise genetic relatedness was estimated between individuals based on their whole-genome array data using a mixed linear model. Heritability was estimated separately for young-onset stroke and old-onset stroke (age ≥ 55 years). RESULTS: Heritabilities for young-onset stroke and old-onset stroke were estimated at 42% (±8%, P < 0.001) and 34% (±10%, P < 0.001), respectively. CONCLUSIONS: Our data suggest that the genetic contribution to the risk of stroke may be higher in young-onset ischaemic stroke, although the difference was not statistically significant.

Endovascular Recanalization in Acute Ischemic Stroke Using the Solitaire FR Revascularization Device with Adjunctive C-Arm CT Imaging.

In this clinical report, we examined a single-center experience by using the Solitaire FR Revascularization Device in the treatment of acute ischemic stroke in which there was poor initial visualization of the occluded arterial branches by using biplanar cerebral angiography. In all cases, adjunctive C-arm CT was used during the deployment of the thrombectomy device to gain additional information regarding device placement and expansion. Outcome measures included the extent of reperfusion, posttreatment changes in NIHSS scores, posttreatment TICI scores, cerebral hemorrhage, and survival. Clot removal with successful arterial recanalization was achieved in 15/18 cases (83.3%) with TICI scores of 2b/3 in all patients who had initial recanalization. The NIHSS score improved, on average, from 19 pretreatment to 11 posttreatment, and 72% of patients survived. In cases of acute stroke in which there is little information available regarding the positioning and deployment of a retrievable stent during mechanical thrombectomy, the use of C-arm CT may provide more information about device placement across an area of thrombus.

Effect of structural remodeling (retraction and recoil) of the pipeline embolization device on aneurysm occlusion rate.

BACKGROUND AND PURPOSE: During endovascular treatment of unruptured aneurysms with the Pipeline Embolization Device, an oversized device is often selected to achieve better wall apposition; however, this device oversizing could be related to overelongation and possible delayed enlargement of the stented region. The purpose of this study is to investigate the relationship between oversize and treatment outcome. MATERIALS AND METHODS: The DynaCT images of 14 aneurysms treated by a single Pipeline Embolization Device were retrospectively analyzed. 3D images of the deployed device were compared with those acquired at the 6-month follow-up for qualitative and quantitative evaluation. The diameter and length of the Pipeline Embolization Device were measured at both time points and compared for determination of the device changes. RESULTS: Structural changes of the device have been observed, and it was found that the Pipeline Embolization Device influences the vessel curvature in some cases. On average, it increases its diameter by 0.23 mm and decreases its length by 2.88 mm within 6 months of initial deployment. Excessive elongation beyond its nominal length is correlated with a lower aneurysm occlusion rate at the 6-month follow-up. CONCLUSIONS: Not only does a Pipeline Embolization Device reconstruct the aneurysm and parent artery, but its entire structure goes through a gradual remodeling process. The relative deformation between the device and the artery indicates suboptimal wall apposition. Device oversizing does not have a direct effect on shortening or recoil. The aneurysm occlusion rate, however, is lowered by overelongation of the Pipeline Embolization Device.

Determinants of intrathoracic adipose tissue volume and associations with cardiovascular disease risk factors in Amish.

BACKGROUND AND AIM: Hypothesizing that intrathoracic fat might exert local effects on the coronary vasculature, we assessed the association of intrathoracic fat volume and its two subcomponents with coronary artery calcification (CAC) in 909 relatively healthy Amish adults. METHODS AND RESULTS: Intrathoracic fat, which is comprised of fat between the surface of the heart and the visceral epicardium (epicardial fat) and fat around the heart but outside of the fibrous pericardium (pericardial fat), was measured from electron beam CT scans. We examined the association between intrathoracic fat volume and cardiovascular disease risk factors in multivariate regression model. Fat volume in the epicardial and pericardial compartments were highly correlated with each other and with body mass index. Neither CAC extent nor CAC presence (Agatston score > 0) was associated with increased intrathoracic fat volume in sex-stratified models adjusting for age (p > 0.10). Intrathoracic fat volume was significantly correlated with higher systolic/diastolic blood pressure, pulse pressure, fasting glucose, insulin, triglyceride and lower high-density lipoprotein cholesterol in sex-stratified models adjusting for age (p < 0.05). However, associations were attenuated after further adjustment for body mass index. CONCLUSIONS: These data do not provide support for a significant role for intrathoracic fat in the development of CAC.

The CYP2C19*17 variant is not independently associated with clopidogrel response.

BACKGROUND: Cytochrome P450 2C19 (CYP2C19) is the principal enzyme responsible for converting clopidogrel into its active metabolite, and common genetic variants have been identified, most notably CYP2C19*2 and CYP2C19*17, that are believed to alter its activity and expression, respectively. OBJECTIVE: We evaluated whether the consequences of the CYP2C19*2 and CYP2C19*17 variants on clopidogrel response were independent of each other or genetically linked through linkage disequilibrium (LD). PATIENTS/METHODS: We genotyped the CYP2C19*2 and CYP2C19*17 variants in 621 members of the Pharmacogenomics of Anti-Platelet Intervention (PAPI) Study and evaluated the effects of these polymorphisms singly and then jointly, taking into account LD, on clopidogrel prodrug level, clopidogrel active metabolite level, and adenosine 5'-diphosphate (ADP)-stimulated platelet aggregation before and after clopidogrel exposure. RESULTS: The CYP2C19*2 and CYP2C19*17 variants were in LD (|D'| = 1.0; r(2)  = 0.07). In association analyses that did and did not account for the effects of CYP2C19*17, CYP2C19*2 was strongly associated with levels of clopidogrel active metabolite (ß = -5.24, P = 3.0 × 10(-9) and ß = -5.36, P = 3.3 × 10(-14) , respectively) and posttreatment ADP-stimulated platelet aggregation (ß = 7.55, P = 2.9 × 10(-16) and ß = 7.51, P = 7.0 × 10(-15) , respectively). In contrast, CYP2C19*17 was marginally associated with clopidogrel active metabolite levels and ADP-stimulated platelet aggregation before (ß = 1.57, P = 0.04 and ß = -1.98, P = 0.01, respectively) but not after (ß = 0.40, P = 0.59 and ß = -0.13, P = 0.69, respectively) adjustment for the CYP2C19*2 variant. Stratified analyses of CYP2C19*2/CYP2C19*17 genotype combinations revealed that CYP2C19*2, and not CYP2C19*17, was the primary determinant in altering clopidogrel response. CONCLUSIONS: Our results suggest that CYP2C19*17 has a small (if any) effect on clopidogrel-related traits and that the observed effect of this variant is due to LD with the CYP2C19*2 loss-of-function variant.

Surgical treatment for combined hemifacial spasm and atypical trigeminal neuralgia caused by a tortuous basilar artery. Case report and review of the literature.

Simultaneous hemifacial spasm (HFS) and trigeminal neuralgia caused by cranial nerve (CN) compression from a tortuous basilar artery (BA) is very rare. We report a case of a 66-year-old man who presented with both HFS and "atypical" trigeminal neuralgia. The patient had a tortuous BA compressing both CN V and VII. The patient underwent microvascular decompression after failing conservative medical management. To the best of our knowledge this is the first reported case of both HFS and "atypical" trigeminal neuralgia that were both successfully treated by surgical intervention. We report the management of this rare combination and review the literature.

Paraoxonase 1 (PON1) gene variants are not associated with clopidogrel response.

A common functional variant in paraoxonase 1 (PON1), Q192R, was recently reported to be a major determinant of clopidogrel response. This variant was genotyped in 566 participants of the Amish Pharmacogenomics of Anti-Platelet Intervention (PAPI) study and in 227 percutaneous coronary intervention (PCI) patients. Serum paraoxonase activity was measured in a subset of 79 PAPI participants. PON1 Q192R was not associated with pre- or post-clopidogrel platelet aggregation in the PAPI study (P = 0.16 and P = 0.21, respectively) or the PCI cohort (P = 0.47 and P = 0.91, respectively). The Q192 allele was not associated with cardiovascular events (hazard ratio (HR) 0.46, 95% confidence interval (CI) 0.20-1.06; P = 0.07). No correlation was observed between paraoxonase activity and post-clopidogrel platelet aggregation (r(2) < 0.01, P = 0.78). None of 49 additional PON1 variants evaluated was associated with post-clopidogrel platelet aggregation. These findings do not support a role for PON1 as a determinant of clopidogrel response.

Ewing sarcoma mimicking a peripheral nerve sheath tumor.

We describe the first patient with an extradural, extramedullary Ewing's sarcoma tumor mimicking a nerve sheath tumor with no overt evidence of metastasis. A 28-year-old woman with no past medical history presented with a progressive 3-year history of low back pain and right-sided lower extremity radiculopathy after having failed conservative therapies. MRI of the lumbar spine revealed a right-sided enhancing, dumbbell-shaped lesion at the right neural foramen appearing to originate from the L4 nerve root, suspicious for a peripheral nerve sheath tumor or schwannoma. The patient and findings are discussed in the context of the literature, including an update on the relatively recent diagnostic redesignation of the Ewing's sarcoma family tumors.

Autosome-wide linkage analysis of hip structural phenotypes in the Old Order Amish.

INTRODUCTION: Fracture risk is associated with bone mineral density (BMD) and with other indices of bone strength, including hip geometry. While the heritability and associated fracture risk of BMD are well described, less is known about genetic influences of bone geometry. We derived hip structural phenotypes using the Hip Structural Analysis program (HSA) and performed autosome-wide linkage analysis of hip geometric structural phenotypes. MATERIALS AND METHODS: The Amish Family Osteoporosis Study was designed to identify genes affecting bone health. BMD was measured at the hip using dual X-ray absorptiometry (DXA) in 879 participants (mean age+/-SD=49.8+/-16.1 years, range 18-91 years) from large multigenerational families. From DXA scans, we computed structural measures of hip geometry at the femoral neck (NN) and shaft (S) by HSA, including cross-sectional area (CSA), endocortical or inner diameter (ID), outer diameter (OD) buckling ratio (BR) and section modulus (Z). Genotyping of 731 highly polymorphic microsatellite markers (average spacing of 5.4 cM) and autosome-wide multipoint linkage analysis was performed. RESULTS: The heritability of HSA-derived hip phenotypes ranged from 40 to 84%. In the group as a whole, autosome-wide linkage analysis suggested evidence of linkage for QTLs related to NN_Z on chromosome 1p36 (LOD=2.36). In subgroup analysis, ten additional suggestive regions of linkage were found on chromosomes 1, 2, 5, 6, 11, 12, 14, 15 and 17, all with LOD>2.3 except for our linkage at 17q11.2-13 for men and women age 50 and under for NN_CSA, which had a lower LOD of 2.16, but confirmed a previous linkage report. CONCLUSIONS: We found HSA-derived measures of hip structure to be highly heritable independent of BMD. No strong evidence of linkage was found for any phenotype. Confirmatory evidence of linkage was found on chromosome 17q11.2-12 for NN_CSA. Modest evidence was found for genes affecting hip structural phenotypes at ten other chromosomal locations.

Genetic influences on bone loss in the San Antonio Family Osteoporosis study.

UNLABELLED: The genetic contribution to age-related bone loss is not well understood. We estimated that genes accounted for 25-45% of variation in 5-year change in bone mineral density in men and women. An autosome-wide linkage scan yielded no significant evidence for chromosomal regions implicated in bone loss. INTRODUCTION: The contribution of genetics to acquisition of peak bone mass is well documented, but little is known about the influence of genes on subsequent bone loss with age. We therefore measured 5-year change in bone mineral density (BMD) in 300 Mexican Americans (>45 years of age) from the San Antonio Family Osteoporosis Study to identify genetic factors influencing bone loss. METHODS: Annualized change in BMD was calculated from measurements taken 5.5 years apart. Heritability (h(2)) of BMD change was estimated using variance components methods and autosome-wide linkage analysis was carried out using 460 microsatellite markers at a mean 7.6 cM interval density. RESULTS: Rate of BMD change was heritable at the forearm (h(2) = 0.31, p = 0.021), hip (h(2) = 0.44, p = 0.017), spine (h(2) = 0.42, p = 0.005), but not whole body (h(2) = 0.18, p = 0.123). Covariates associated with rapid bone loss (advanced age, baseline BMD, female sex, low baseline weight, postmenopausal status, and interim weight loss) accounted for 10% to 28% of trait variation. No significant evidence of linkage was observed at any skeletal site. CONCLUSIONS: This is one of the first studies to report significant heritability of BMD change for weight-bearing and non-weight-bearing bones in an unselected population and the first linkage scan for change in BMD.

Accounting for relatedness in family based genetic association studies.

OBJECTIVE: Assess the differences in point estimates, power and type 1 error rates when accounting for and ignoring family structure in genetic tests of association. METHODS: We compare by simulation the performance of analytic models using variance components to account for family structure and regression models that ignore relatedness for a range of possible family based study designs (i.e., sib pairs vs. large sibships vs. nuclear families vs. extended families). RESULTS: Our analyses indicate that effect size estimates and power are not significantly affected by ignoring family structure. Type 1 error rates increase when family structure is ignored, as density of family structures increases, and as trait heritability increases. For discrete traits with moderate levels of heritability and across many common sampling designs, type 1 error rates rise from a nominal 0.05 to 0.11. CONCLUSION: Ignoring family structure may be useful in screening although it comes at a cost of a increased type 1 error rate, the magnitude of which depends on trait heritability and pedigree configuration.

Betacellulin variants and type 2 diabetes in the Old Order Amish.

Betacellulin is a member of the epidermal growth factor (EGF) family and may play a role in islet neogenesis and regeneration. To evaluate whether polymorphisms in this gene are associated with type 2 diabetes (T2DM) and impaired glucose tolerance (IGT), we genotyped 7 previously identified betacellulin variants in Amish subjects with T2DM (n=150), IGT (n=148) and normal glucose tolerance (NGT) (n=361). There were no significant differences in the allele frequencies of the variants among the 3 groups. In an expanded set of 729 nondiabetic Amish subjects, there was no significant association between the betacellulin variants and levels of glucose or insulin either fasting or during a 3 h oral glucose tolerance test, HOMA or insulin secretion index. These results are consistent with previous studies in Caucasian populations and suggest that variants in the betacellulin gene do not play a major role in the development of T2DM in Caucasian populations.

Relationship between vascular calcification and bone mineral density in the Old-order Amish.

Vascular calcification and osteoporosis are common age-related processes that are influenced by both genetic and nongenetic factors. Whether common genes underlie these processes is not known. We measured coronary artery calcification (CAC), aortic calcification (AC), and bone mineral density (BMD) in 682 men and women from large Old-Order Amish families. We assessed the heritabilities of these traits and then evaluated, using variance decomposition procedures, whether variation in the traits was influenced by a common set of genes (i.e., pleiotropy). Significant heritabilities were detected for BMD of the femoral neck and spine (0.65, 0.63) and CAC and AC (0.43, 0.42). Mean BMD did not differ significantly across quartiles of either CAC or AC in either sex. In neither the total group nor any single subgroup (men, women, postmenopausal women) did any of the genetic or environmental correlations between BMD and vascular calcification achieve statistical significance. However, subjects with a history of cardiovascular disease (CVD) events had significantly lower BMD at the femoral neck compared to subjects who reported no prior history of CVD (age-, sex-, body mass index-, and family structure-adjusted P = 0.003). We detected no evidence for shared genes affecting the joint distribution of bone and vascular calcification. However, our results do reveal a lower BMD in subjects with a prior history of CVD in the Old-Order Amish.

Meta-analysis of five genome-wide linkage studies for body mass index reveals significant evidence for linkage to chromosome 8p.

OBJECTIVE: To perform a meta-analysis of genome-wide linkage scans using body mass index (BMI) to identify genetic loci predisposing to obesity. DATA: A total of 13 published genome scans on obesity have used BMI as their primary end point. Five of these 13 groups agreed to provide detailed results from their scans that were required for a meta-analysis. Collectively, these five studies included a total of 2814 individuals from 505 families. METHODS: The results of the five studies were analysed using the GSMA (genome scans meta-analysis) method. RESULTS: The analysis revealed significant evidence for linkage of the quantitative phenotype BMI to 8p (P<0.0005).