Susanne Moebus

Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease.

We undertook a two-stage genome-wide association study (GWAS) of Alzheimers disease (AD) involving over 16,000 individuals, the most powerful AD GWAS to date. In stage 1 (3,941 cases and 7,848 controls), we replicated the established association with the apolipoprotein E (APOE) locus (most significant SNP, rs2075650, P = 1.8 × 10−157) and observed genome-wide significant association with SNPs at two loci not previously associated with the disease: at the CLU (also known as APOJ) gene (rs11136000, P = 1.4 × 10−9) and 5′ to the PICALM gene (rs3851179, P = 1.9 × 10−8). These associations were replicated in stage 2 (2,023 cases and 2,340 controls), producing compelling evidence for association with Alzheimers disease in the combined dataset (rs11136000, P = 8.5 × 10−10, odds ratio = 0.86; rs3851179, P = 1.3 × 10−9, odds ratio = 0.86).

Letter abstract - Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's Disease

We undertook a two-stage genome-wide association study (GWAS) of Alzheimers disease (AD) involving over 16,000 individuals, the most powerful AD GWAS to date. In stage 1 (3,941 cases and 7,848 controls), we replicated the established association with the apolipoprotein E (APOE) locus (most significant SNP, rs2075650, P = 1.8 × 10−157) and observed genome-wide significant association with SNPs at two loci not previously associated with the disease: at the CLU (also known as APOJ) gene (rs11136000, P = 1.4 × 10−9) and 5′ to the PICALM gene (rs3851179, P = 1.9 × 10−8). These associations were replicated in stage 2 (2,023 cases and 2,340 controls), producing compelling evidence for association with Alzheimers disease in the combined dataset (rs11136000, P = 8.5 × 10−10, odds ratio = 0.86; rs3851179, P = 1.3 × 10−9, odds ratio = 0.86).

Coronary Risk Stratification, Discrimination, and Reclassification Improvement Based on Quantification of Subclinical Coronary Atherosclerosis: The Heinz Nixdorf Recall Study

OBJECTIVES The purpose of this study was to determine net reclassification improvement (NRI) and improved risk prediction based on coronary artery calcification (CAC) scoring in comparison with traditional risk factors. BACKGROUND CAC as a sign of subclinical coronary atherosclerosis can noninvasively be detected by CT and has been suggested to predict coronary events. METHODS In 4,129 subjects from the HNR (Heinz Nixdorf Recall) study (age 45 to 75 years, 53% female) without overt coronary artery disease at baseline, traditional risk factors and CAC scores were measured. Their risk was categorized into low, intermediate, and high according to the Framingham Risk Score (FRS) and National Cholesterol Education Panel Adult Treatment Panel (ATP) III guidelines, and the reclassification rate based on CAC results was calculated. RESULTS After 5 years of follow-up, 93 coronary deaths and nonfatal myocardial infarctions occurred (cumulative risk 2.3%; 95% confidence interval: 1.8% to 2.8%). Reclassifying intermediate (defined as 10% to 20% and 6% to 20%) risk subjects with CAC <100 to the low-risk category and with CAC ≥400 to the high-risk category yielded an NRI of 21.7% (p = 0.0002) and 30.6% (p < 0.0001) for the FRS, respectively. Integrated discrimination improvement using FRS variables and CAC was 1.52% (p < 0.0001). Adding CAC scores to the FRS and National Cholesterol Education Panel ATP III categories improved the area under the curve from 0.681 to 0.749 (p < 0.003) and from 0.653 to 0.755 (p = 0.0001), respectively. CONCLUSIONS CAC scoring results in a high reclassification rate in the intermediate-risk cohort, demonstrating the benefit of imaging of subclinical coronary atherosclerosis. Our study supports its application, especially in carefully selected individuals with intermediate risk.

Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease.

Background Late Onset Alzheimers disease (LOAD) is the leading cause of dementia. Recent large genome-wide association studies (GWAS) identified the first strongly supported LOAD susceptibility genes since the discovery of the involvement of APOE in the early 1990s. We have now exploited these GWAS datasets to uncover key LOAD pathophysiological processes. Methodology We applied a recently developed tool for mining GWAS data for biologically meaningful information to a LOAD GWAS dataset. The principal findings were then tested in an independent GWAS dataset. Principal Findings We found a significant overrepresentation of association signals in pathways related to cholesterol metabolism and the immune response in both of the two largest genome-wide association studies for LOAD. Significance Processes related to cholesterol metabolism and the innate immune response have previously been implicated by pathological and epidemiological studies of Alzheimers disease, but it has been unclear whether those findings reflected primary aetiological events or consequences of the disease process. Our independent evidence from two large studies now demonstrates that these processes are aetiologically relevant, and suggests that they may be suitable targets for novel and existing therapeutic approaches.

Residential Exposure to Traffic Is Associated With Coronary Atherosclerosis

Background— Long-term exposure to fine-particulate-matter (PM2.5) air pollution may accelerate the development and progression of atherosclerosis. We investigated the associations of long-term residential exposure to traffic and fine particulate matter with the degree of coronary atherosclerosis. Methods and Results— We used baseline data on 4494 participants (age 45 to 74 years) from the German Heinz Nixdorf Recall Study, a population-based, prospective cohort study that started in 2000. To assess exposure differences, distances between residences and major roads were calculated, and annual fine particulate matter concentrations, derived from a small-scale dispersion model, were assigned to each address. The main outcome was coronary artery calcification (CAC) assessed by electron-beam computed tomography. We evaluated the association between air pollution and CAC with logistic and linear regression analyses, controlling for individual level risk factors of coronary atherosclerosis. Compared with participants living >200 m away from a major road, participants living within 50, 51 to 100, and 101 to 200 m had odds ratios of 1.63 (95% CI, 1.14 to 2.33), 1.34 (95% CI, 1.00 to 1.79), and 1.08 (95% CI, 0.85 to 1.39), respectively, for a high CAC (CAC above the age- and gender-specific 75th percentile). A reduction in the distance between the residence and a major road by half was associated with a 7.0% (95% CI, 0.1 to 14.4) higher CAC. Fine particulate matter exposure was associated with CAC only in subjects who had not been working full-time for at least 5 years. Conclusions— Long-term residential exposure to high traffic is associated with the degree of coronary atherosclerosis.

Common variants in KCNN3 are associated with lone atrial fibrillation

Atrial fibrillation (AF) is the most common sustained arrhythmia. Previous studies have identified several genetic loci associated with typical AF. We sought to identify common genetic variants underlying lone AF. This condition affects a subset of individuals without overt heart disease and with an increased heritability of AF. We report a meta-analysis of genome-wide association studies conducted using 1,335 individuals with lone AF (cases) and 12,844 unaffected individuals (referents). Cases were obtained from the German AF Network, Heart and Vascular Health Study, the Atherosclerosis Risk in Communities Study, the Cleveland Clinic and Massachusetts General Hospital. We identified an association on chromosome 1q21 to lone AF (rs13376333, adjusted odds ratio = 1.56; P = 6.3 × 10−12), and we replicated this association in two independent cohorts with lone AF (overall combined odds ratio = 1.52, 95% CI 1.40–1.64; P = 1.83 × 10−21). rs13376333 is intronic to KCNN3, which encodes a potassium channel protein involved in atrial repolarization.

Key susceptibility locus for nonsyndromic cleft lip with or without cleft palate on chromosome 8q24.

We conducted a genome-wide association study involving 224 cases and 383 controls of Central European origin to identify susceptibility loci for nonsyndromic cleft lip with or without cleft palate (NSCL/P). A 640-kb region at chromosome 8q24.21 was found to contain multiple markers with highly significant evidence for association with the cleft phenotype, including three markers that reached genome-wide significance. The 640-kb cleft-associated region was saturated with 146 SNP markers and then analyzed in our entire NSCL/P sample of 462 unrelated cases and 954 controls. In the entire sample, the most significant SNP (rs987525) had a P value of 3.34 × 10−24. The odds ratio was 2.57 (95% CI = 2.02–3.26) for the heterozygous genotype and 6.05 (95% CI = 3.88–9.43) for the homozygous genotype. The calculated population attributable risk for this marker is 0.41, suggesting that this study has identified a major susceptibility locus for NSCL/P.

Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1

Migraine is a common episodic neurological disorder, typically presenting with recurrent attacks of severe headache and autonomic dysfunction. Apart from rare monogenic subtypes, no genetic or molecular markers for migraine have been convincingly established. We identified the minor allele of rs1835740 on chromosome 8q22.1 to be associated with migraine (P = 5.38 × 10−9, odds ratio = 1.23, 95% CI 1.150–1.324) in a genome-wide association study of 2,731 migraine cases ascertained from three European headache clinics and 10,747 population-matched controls. The association was replicated in 3,202 cases and 40,062 controls for an overall meta-analysis P value of 1.69 × 10−11 (odds ratio = 1.18, 95% CI 1.127–1.244). rs1835740 is located between MTDH (astrocyte elevated gene 1, also known as AEG-1) and PGCP (encoding plasma glutamate carboxypeptidase). In an expression quantitative trait study in lymphoblastoid cell lines, transcript levels of the MTDH were found to have a significant correlation to rs1835740 (P = 3.96 × 10−5, permuted threshold for genome-wide significance 7.7 × 10−5). To our knowledge, our data establish rs1835740 as the first genetic risk factor for migraine.

Genome-wide association study identifies two susceptibility loci for nonsyndromic cleft lip with or without cleft palate

We conducted a genome-wide association study for nonsyndromic cleft lip with or without cleft palate (NSCL/P) in 401 affected individuals and 1,323 controls, with replication in an independent sample of 793 NSCL/P triads. We report two new loci associated with NSCL/P at 17q22 (rs227731, combined P = 1.07 × 10−8, relative risk in homozygotes = 1.84, 95% CI 1.34–2.53) and 10q25.3 (rs7078160, combined P = 1.92 × 10−8, relative risk in homozygotes = 2.17, 95% CI 1.32–3.56).

Two new Loci for body-weight regulation identified in a joint analysis of Genome-Wide Association Studies for Early-Onset Extreme Obesity in French and German Study Groups

Meta-analyses of population-based genome-wide association studies (GWAS) in adults have recently led to the detection of new genetic loci for obesity. Here we aimed to discover additional obesity loci in extremely obese children and adolescents. We also investigated if these results generalize by estimating the effects of these obesity loci in adults and in population-based samples including both children and adults. We jointly analysed two GWAS of 2,258 individuals and followed-up the best, according to lowest p-values, 44 single nucleotide polymorphisms (SNP) from 21 genomic regions in 3,141 individuals. After this DISCOVERY step, we explored if the findings derived from the extremely obese children and adolescents (10 SNPs from 5 genomic regions) generalized to (i) the population level and (ii) to adults by genotyping another 31,182 individuals (GENERALIZATION step). Apart from previously identified FTO, MC4R, and TMEM18, we detected two new loci for obesity: one in SDCCAG8 (serologically defined colon cancer antigen 8 gene; p = 1.85×10−8 in the DISCOVERY step) and one between TNKS (tankyrase, TRF1-interacting ankyrin-related ADP-ribose polymerase gene) and MSRA (methionine sulfoxide reductase A gene; p = 4.84×10−7), the latter finding being limited to children and adolescents as demonstrated in the GENERALIZATION step. The odds ratios for early-onset obesity were estimated at ∼1.10 per risk allele for both loci. Interestingly, the TNKS/MSRA locus has recently been found to be associated with adult waist circumference. In summary, we have completed a meta-analysis of two GWAS which both focus on extremely obese children and adolescents and replicated our findings in a large followed-up data set. We observed that genetic variants in or near FTO, MC4R, TMEM18, SDCCAG8, and TNKS/MSRA were robustly associated with early-onset obesity. We conclude that the currently known major common variants related to obesity overlap to a substantial degree between children and adults.