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Genome-wide association studies have identified a region on chromosome 9p that is associated with coronary artery disease (CAD). The region is also associated with type 2 diabetes (T2D), a risk factor for CAD, although different SNPs were reported to be associated to each disease in separate studies. We have undertaken a case-control study in 4251 CAD cases and 4443 controls in four European populations using previously reported ('literature') and tagging SNPs. We replicated the literature SNPs (P = 8 x 10^-13; OR = 1.29; 95% CI: 1.20- 1.38) and showed that the strong consistent association detected by these SNPs is a consequence of a 'ying-yang' haplotype pattern spanning 53 kb. There was no evidence of additional CAD susceptibility alleles over the major risk haplotype. CAD patients without myocardial infarction (MI) showed a trend towards stronger association than MI patients. The CAD susceptibility conferred by this locus did not differ by sex, age, smoking, obesity, hypertension or diabetes. A simultaneous test of CAD and diabetes susceptibility with CAD and T2D-associated SNPs indicated that these associations were independent of each other. Moreover, this region was not associated with differences in plasma levels of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, fibrinogen, albumin, uric acid, bilirubin or homocysteine, although the CAD-high-risk allele was paradoxically associated with lower triglycerine levels. A large antisense non-coding RNA gene (ANRIL) collocates with the high-risk haplotype, is expressed in tissues and cell types that are affected by atherosclerosis and is a prime candidate gene for the chromosome 9p CAD locus.

We have created a global map of the effects of polymorphism on gene expression in 400 children from families recruited through a proband with asthma. We genotyped 408,273 SNPs and identified expression quantitative trait loci from measurements of 54,675 transcripts representing 20,599 genes in Epstein-Barr virus‐transformed lymphoblastoid cell lines. We found that 15,084 transcripts (28%) representing 6,660 genes had narrow-sense heritabilities (H 2 ) 4 0.3. We executed genome-wide association scans for these traits and found peak lod scores between 3.68 and 59.1. The most highly heritable traits were markedly enriched in Gene Ontology descriptors for response to unfolded protein (chaperonins and heat shock proteins), regulation of progression through the cell cycle, RNA processing, DNA repair, immune responses and apoptosis. SNPs that regulate expression of these genes are candidates in the study of degenerative diseases, malignancy, infection and inflammation. We have created a downloadable database to facilitate use of our findings in the mapping of complex disease loci. Variation in gene transcription is important in mediating disease susceptibility, and global identification of genetic variants that regulate gene transcription will be helpful in mapping human disease genes. The many genome-wide association (GWA) studies currently underway are likely to identify multiple genetic variants that are associated with multifactorial traits. We anticipate that these variants will often reside outside of coding regions and will have no known or evident functional effects. Gene transcript abundance is directly modified by polymorphism in regulatory elements and consequently may be mapped with considerable power 1,2 . As a consequence, our objective was to build a database that would allow researchers to systematically examine potential effects of disease-associated variants on transcript expression. By studying global gene expression in a comprehensive GWA study, we also hoped to add global understanding to issues of heritability, marker coverage, interactions and dominance that are of relevance to all GWA studies of complex traits.

BACKGROUND: Diabetic nephropathy is likely to be a complex genetic trait. To date, most diabetic nephropathy candidate gene studies have tested a limited number of genes and variants in small sized populations, or in populations that were poorly matched or phenotyped. The main objective of the EURAGEDIC study was to address these problems. METHODS: Single nucleotide polymorphisms (SNPs) in candidate genes were tested for association with overt diabetic nephropathy (persistent albuminuria >300 mg/24 h) in a large (n=2499) Type 1 diabetes case/control study. Testing for transmission disequilibrium in 541 independent parent-offspring trios with or without diabetic nephropathy was applied for validation of consistency. Candidate genes were selected based on previous linkage studies, knowledge of metabolic pathways, and animal models. A comprehensive SNP discovery in more than 100 candidate genes was performed by direct sequencing. RESULTS: In total, 1176 cases with diabetic nephropathy and 1323 diabetic controls with longstanding normoalbuminuria were included from three European populations (Denmark, Finland, France). Data were collected on HbA(1c), blood pressure, urinary albumin excretion rate, kidney function, retinopathy, smoking, medication and cardiovascular disease. To summarize the relevant non-genetic predictors for diabetic nephropathy a baseline phenotypic model fitted to EURAGEDIC data included the covariates: sex, diabetes duration, HbA(1c) and smoking as well as pair-wise interactions. CONCLUSIONS: The EURAGEDIC study is designed and powered to identify and validate common alleles as genetic risk factors for diabetic nephropathy in Type 1 diabetic patients.

Individual variation in fetal hemoglobin (HbF, α 2 γ 2 ) response underlies the remarkable diversity in phenotypic severity of sickle cell disease and β thalassemia. HbF levels and HbF-associated quantitative traits (e.g., F cell levels) are highly heritable. We have previously mapped a major quantitative trait locus (QTL) controlling F cell levels in an extended Asian-Indian kindred with β thalassemia to a 1.5-Mb interval on chromosome 6q23, but the causative gene(s) are not known. The QTL encompasses several genes including HBS1L , a member of the GTP-binding protein family that is expressed in erythroid progenitor cells. In this high-resolution association study, we have identified multiple genetic variants within and 5′ to HBS1L at 6q23 that are strongly associated with F cell levels in families of Northern European ancestry ( P = 10 −75 ). The region accounts for 17.6% of the F cell variance in northern Europeans. Although mRNA levels of HBS1L and MYB in erythroid precursors grown in vitro are positively correlated, only HBS1L expression correlates with high F cell alleles. The results support a key role for the HBS1L -related genetic variants in HbF control and illustrate the biological complexity of the mechanism of 6q QTL as a modifier of fetal hemoglobin levels in the β hemoglobinopathies.

Rates of childhood asthma diagnosis are rising: 6% of children in the United States are sufferers. Both genetic and environmental factors are clearly important. To discover more about the genetic element, Moffatt et al. looked for genes linked to asthma in a genome-wide association scan. More than a third of children with asthma of onset below the age of seven showed variations in expression of the ORMDL3 gene on chromosome 17. Similar genes are found in yeast and other primitive organisms, suggesting that they may be components of an ancient and conserved immune mechanism. Variations in expression of the gene ORMDL3 were found to be associated with development of childhood asthma, suggesting this gene should be examined in more patient groups. Asthma is caused by a combination of poorly understood genetic and environmental factors1,2. We have systematically mapped the effects of single nucleotide polymorphisms (SNPs) on the presence of childhood onset asthma by genome-wide association. We characterized more than 317,000 SNPs in DNA from 994 patients with childhood onset asthma and 1,243 non-asthmatics, using family and case-referent panels. Here we show multiple markers on chromosome 17q21 to be strongly and reproducibly associated with childhood onset asthma in family and case-referent panels with a combined P value of P

Angiotensin 1-converting enzyme gene (ACE) is a risk factor for diabetic nephropathy (DN) in patients with type 1 diabetes. The selection of this candidate gene is supported by cross-sectional and follow-up studies, but no convincing family-based studies are available. Recruited were 1057 patients (with DN: persistent albuminuria with or without renal failure) and 1127 control subjects (long-standing [> or =15 yr] normoalbuminuric patients with type 1 diabetes) in Denmark, Finland, and France and 532 family trios that were composed of 244 trios with DN probands and 288 trios with non-DN probands. Five ACE polymorphisms were studied. In the case-control analysis, the rs1800764-C, rs4311-T, Insertion/deletion (I/D or rs1799752)-D, rs4366-G, and rs12449782-G alleles were associated with an increased risk for DN, homogeneously across populations, with allelic odds ratios of 1.11 (95% confidence interval 1.00 to 1.22), 1.18 (1.04 to 1.33), 1.13 (1.02 to 1.23), 1.10 (0.99 to 1.20), and 1.12 (1.01 to 1.23), respectively. Haplotype analysis further demonstrated that the haplotype defined by the D, rs4366_G and rs12449782_G alleles was associated with a greater risk for DN. Even though no significant allelic overtransmission to DN or non-DN probands was detected, the family-based study provided consistent results with the case-control analysis. In a large case-control study, it was shown that the ACE polymorphisms were associated with DN; these findings were not confirmed in a family-based association study. This study population is suitable to search for additional candidate genes for DN.

Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of ∼185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 < MAF < 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.

Background: Patients who have suffered from cerebral ischemia have a high risk of recurrent vascular events. Predictive models based on classical risk factors typically have limited prognostic value. Given that cerebral ischemia has a heritable component, genetic information might improve performance of these risk models. Our aim was to develop and compare two models: one containing traditional vascular risk factors, the other also including genetic information. Methods and Results: We studied 1020 patients with cerebral ischemia and genotyped them with the Illumina Immunochip. Median follow-up time was 6.5 years; the annual incidence of new ischemic events (primary outcome, n=198) was 3.0%. The prognostic model based on classical vascular risk factors had an area under the receiver operating characteristics curve (AUC-ROC) of 0.65 (95% confidence interval 0.61-0.69). When we added a genetic risk score based on prioritized SNPs from a genome-wide association study of ischemic stroke (using summary statistics from the METASTROKE study which included 12389 cases and 62004 controls), the AUC-ROC remained the same. Similar results were found for the secondary outcome ischemic stroke. Conclusions: We found no additional value of genetic information in a prognostic model for the risk of ischemic events in patients with cerebral ischemia of arterial origin. This is consistent with a complex, polygenic architecture, where many genes of weak effect likely act in concert to influence the heritable risk of an individual to develop (recurrent) vascular events. At present, genetic information cannot help clinicians to distinguish patients at high risk for recurrent vascular events.

Objective:To quantify genetic overlap between migraine and ischemic stroke (IS) with respect to common genetic variation.Methods:We applied 4 different approaches to large-scale meta-analyses of genome-wide data on migraine (23,285 cases and 95,425 controls) and IS (12,389 cases and 62,004 controls). First, we queried known genome-wide significant loci for both disorders, looking for potential overlap of signals. We then analyzed the overall shared genetic load using polygenic scores and estimated the genetic correlation between disease subtypes using data derived from these models. We further interrogated genomic regions of shared risk using analysis of covariance patterns between the 2 phenotypes using cross-phenotype spatial mapping.Results:We found substantial genetic overlap between migraine and IS using all 4 approaches. Migraine without aura (MO) showed much stronger overlap with IS and its subtypes than migraine with aura (MA). The strongest overlap existed between MO and large artery stroke (LAS; p = 6.4 x 10(-28) for the LAS polygenic score in MO) and between MO and cardioembolic stroke (CE; p = 2.7 x 10(-20) for the CE score in MO).Conclusions:Our findings indicate shared genetic susceptibility to migraine and IS, with a particularly strong overlap between MO and both LAS and CE pointing towards shared mechanisms. Our observations on MA are consistent with a limited role of common genetic variants in this subtype.

Linkage studies have mapped loci for diabetic nephropathy and associated phenotypes on chromosome 3q. We studied 14 plausible candidate genes in the linkage region because of their potential role in vascular complications. In a large-scale study of patients from Denmark, Finland, and France who have type 1 diabetes, 1,057 case and 1,127 control subjects, as well as 532 trios, were investigated for association with diabetic nephropathy. We analyzed 69 haplotype-tagging single nucleotide polymorphisms and nonsynonymous variants that were identified by sequencing. Polymorphisms in three genes, glucose transporter 2 (SLC2A2), kininogen (KNG1), and adiponectin (ADIPOQ), showed nominal association with diabetic nephropathy in single-point analysis. The T-allele of SLC2A2_16459CT was associated with a decreased risk of diabetic nephropathy (odds ratio 0.79 [95% CI 0.66–0.96], P = 0.016), whereas the T-allele of KNG_7965CT and the A-allele of ADIPOQ_prom2GA were associated with increased risk of nephropathy (1.17 [1.03–1.32], P = 0.016; 1.46 [1.11–1.93], P = 0.006, respectively). Analyses of the transmission disequilibrium test showed similar trends only for ADIPOQ_prom2GA with the overtransmission of the A-allele to patients with diabetic nephropathy (1.52 [0.86–2.66], P = NS) and of the G-allele to patients without diabetic nephropathy (0.50 [0.27–0.92], P = 0.026). The overall significance for this variant (nominal P = 0.011) suggests that ADIPOQ might be involved in the development of diabetic nephropathy.

Identification of the genetic influences on human essential hypertension and other complex diseases has proved difficult, partly because of genetic heterogeneity. In many complex-trait resources, additional phenotypic data have been collected, allowing comorbid intermediary phenotypes to be used to characterize more genetically homogeneous subsets. The traditional approach to analyzing covariate-defined subsets has typically depended on researchers' previous expectations for definition of a comorbid subset and leads to smaller data sets, with a concomitant attrition in power. An alternative is to test for dependence between genetic sharing and covariates across the entire data set. This approach offers the advantage of exploiting the full data set and could be widely applied to complex-trait genome scans. However, existing maximum-likelihood methods can be prohibitively computationally expensive, especially since permutation is often required to determine significance. We developed a less computationally intensive score test and applied it to biometric and biochemical covariate data, from 2,044 sibling pairs with severe hypertension, collected by the British Genetics of Hypertension (BRIGHT) study. We found genomewide-significant evidence for linkage with hypertension and several related covariates. The strongest signals were with leaner-body-mass measures on chromosome 20q (maximum LOD = 4.24) and with parameters of renal function on chromosome 5p (maximum LOD = 3.71). After correction for the multiple traits and genetic locations studied, our global genomewide P value was .046. This is the first identity-by-descent regression analysis of hypertension to our knowledge, and it demonstrates the value of this approach for the incorporation of additional phenotypic information in genetic studies of complex traits.

It is well established that gene interactions influence common human diseases, but to date linkage studies have been constrained to searching for single genes across the genome. We applied a novel approach to uncover significant gene-gene interactions in a systematic two-dimensional (2D) genome-scan of essential hypertension. The study cohort comprised 2076 affected sib-pairs and 66 affected half-sib-pairs of the British Genetics of HyperTension study. Extensive simulations were used to establish significance thresholds in the context of 2D genome-scans. Our analyses found significant and suggestive evidence for loci on chromosomes 5, 9,11, 15, 16 and 19, which influence hypertension when gene-gene interactions are taken into account (5q13.1 and 11q22.1, two-locus lod score = 5.72; 5q13.1 and 19q12, two-locus lod score = 5.35; 9q22.3 and 15q12, two-locus lod score = 4.80; 16p12.3 and 16q23.1, two-locus lod score= 4.50). For each significant and suggestive pairwise interaction, the two-locus genetic model that best fitted the data was determined. Regions that were not detected using single-locus linkage analysis were identified in the 2D scan as contributing significant epistatic effects. This approach has discovered novel loci for hypertension and offers a unique potential to use existing data to uncover novel regions involved in complex human diseases.

There is a lack of consistently linked loci influencing blood pressure and hypertension status, and this may be because of genetic or phenotypic heterogeneity. We hypothesize that stratification of subjects by response to antihypertensive drug groups could be used to stringently define subsets that will have reduced genetic and etiologic heterogeneity, by partitioning contrasting mechanisms of hypertension and, thus, enhancing gene finding. We investigated the British Genetics of Hypertension Study population, which is composed of 2142 severely hypertensive white affected sibling pairs. Nonresponse to antihypertensive therapy was defined as an on-treatment blood pressure of >140/90 mm Hg or a difference between prediagnosis and on-treatment blood pressure of P =0.005). This locus may contain a gene for the salt-sensitive form of hypertension and/or a pharmacogenetic locus affecting drug response. We have demonstrated for the first time identification of a significant locus by partitioning different pathways of hypertension using drug response.

Family history is an important independent risk factor for coronary artery disease (CAD), and identification of susceptibility genes for this common, complex disease is a vital goal. Although there has been considerable success in identifying genetic variants that influence well-known risk factors, such as cholesterol levels, progress in unearthing novel CAD genes has been slow. However, advances are now being made through the application of large-scale, systematic, genome-wide approaches. Recent findings particularly highlight the link between CAD and inflammation and immunity, and highlight the biological insights to be gained from a genetic understanding of the world's biggest killer.

Rare mutations in the proopiomelanocortin (POMC) gene cause severe early-onset childhood obesity. However, it is unknown whether common variants in POMC are responsible for variation in body weight or fat distribution within the commonly observed range in the population. We tested for association between three polymorphisms spanning the POMC gene and obesity phenotypes in 1,428 members of 248 families. There was significant association between genotypes at the C8246T (P < 0.0001) and C1032G (P = 0.003) polymorphisms and waist-to-hip ratio (WHR) corrected for age, sex, smoking, exercise, and alcohol consumption. Each T allele at C8246T (or G allele at C1032G) was associated with a 0.2-SD–higher WHR in a codominant fashion. When WHR was additionally corrected for BMI, thus providing a measure of body fat distribution throughout the range of BMI, there remained significant evidence for association with both markers that was of similar magnitude and statistical significance. There was no association between genotype at any polymorphism and BMI or plasma leptin level. These data show that genetic variants at the POMC locus influence body fat distribution within the normal range, suggesting a novel role for POMC in metabolic regulation.

Background: Rare mutations in the leptin ( LEP ) gene cause severe obesity. Common polymorphisms of LEP have been associated with obesity, but their association with cardiovascular disease has been little studied. We have examined the impact of both common and rare polymorphisms of the LEP gene on blood pressure (BP), subclinical atherosclerosis as measured by carotid intima-medial thickness (CIMT), and body mass index (BMI) in a large family study. Methods: Five polymorphisms spanning LEP were typed in 1428 individuals from 248 nuclear families. BP, CIMT, BMI, and plasma leptin were measured. Results: The polymorphisms typed captured all common haplotypes present at LEP . There was strong association between a rare polymorphism in the 3′ untranslated region of LEP (C538T) and both pulse pressure (p = 0.0001) and CIMT (p = 0.008). C/T heterozygotes had a 22% lower pulse pressure and a 17% lower CIMT than C/C homozygotes. The polymorphism accounted for 3–5% of the population variation in pulse pressure and CIMT. There was no association between any LEP polymorphism and either BMI or plasma leptin level. Conclusions: This large family study shows that the rare T allele at the C538T polymorphism of LEP substantially influences pulse pressure and CIMT, but does not appear to exert this effect through actions on plasma leptin level or BMI. This suggests that autocrine or paracrine effects in vascular tissue may be important physiological functions of leptin. This study also provides evidence that rare polymorphisms of particular genes may have substantial effects within the normal range of certain quantitative traits.

The genes in the renin-angiotensin system are important physiologic candidates in studies of the genetic susceptibility to hypertension. Limited information has been available in most studies on the extent of variation in the candidate loci or the modifying effects of different environmental settings. We consequently genotyped 13 polymorphisms at the angiotensin I-converting enzyme (ACE) locus at an average distance of 2 kb in 2776 family members from Nigeria, Jamaica and an African-American community in the US. Allele and haplotype frequencies were similar in the three populations, with modest evidence of European admixture in the US. Two markers were consistently associated with ACE level in the three samples and the proportion of variance accounted for by ACE8 was similar in the three groups. No evidence of consistent association of single markers was noted with blood pressure across the three population samples, however. Likewise, in a haplotype-based analysis, despite significant associations within each population, the findings were not replicated consistently across all three samples. We did observe, however, that the overtransmitted haplotypes among hypertensives were drawn from a single clade, suggesting that susceptibility may cluster in patterns not captured directly by our markers.

It has become commonplace to map individual quantitative trait loci (QTL) in experimental organisms; the means (line-crosses and dense maps of markers) and motivation (the close relationship between continuous physiological traits and common, complex diseases) are self-evident. Progress in mapping human QTL has been more gradual, an inevitable consequence of genetic mapping in a natural population setting. The common objective of these studies has been to understand the molecular mechanisms underlying individual QTL. Recent theoretical and practical advances shift this focus to a more comprehensive or genomic perspective on quantitative variation. Fisher's infinitesimal model of adaptive evolution, which satisfied quantitative geneticists for over 50 years, has been modified in the light of data from QTL mapping experiments in plants and animals. The resulting exponential model provides a pleasing empirical fit to the distribution of QTL effect sizes, predicts that a large amount of quantitative variation will be explained by a limited number of genes and suggests a new mathematical framework for linkage mapping. Molecular analysis of QTL suggests that coding variants (e.g. allozymes) underlie a fraction of quantitative variation and that variants that affect gene expression (expression QTL, eQTL) have a substantial role. This is supported by genomic experiments that combine expression profiling with classical genetic mapping approaches to reveal a remarkable wealth of quantitative heritable variation in the transcriptome and that cis-and trans-acting regulatory factors are organized in networks reflecting pleiotropy. It is hoped that these advances will enhance our understanding of the genetic basis of complex inherited diseases.

Summary Background Blood pressure may contribute to 50% of the global cardiovascular disease epidemic. By understanding the genes predisposing to common disorders such as human essential hypertension we may gain insights into novel pathophysiological mechanisms and potential therapeutic targets. In the Medical Research Council BRItish Genetics of HyperTension (BRIGHT) study, we aim to identify these genetic factors by scanning the human genome for susceptibility genes for essential hypertension. We describe the results of a genome scan for hypertension in a large white European population. Methods We phenotyped 2010 affected sibling pairs drawn from 1599 severely hypertensive families, and completed a 10 centimorgan genome-wide scan. After rigorous quality control, we analysed the genotypic data by non-parametric linkage, which tests whether genes are shared in excess among the affected sibling pairs. Lod scores, calculated at regular points along each chromosome, were used to assess the support for linkage. Findings Linkage analysis identified a principle locus on chromosome 6q, with a lod score of 3·21 that attained genome-wide significance (p=0·042). The inclusion of three further loci with lod scores higher than 1·57 (2q, 5q, and 9q) also show genome-wide significance (p=0·017) when assessed under a locus-counting analysis. Interpretation These findings imply that human essential hypertension has an oligogenic element (a few genes may be involved in determination of the trait) possibly superimposed on more minor genetic effects, and that several genes may be tractable to a positional cloning strategy.

Background Ezetimibe lowers plasma levels of low-density lipoprotein (LDL) cholesterol by inhibiting the activity of the Niemann–Pick C1-like 1 (NPC1L1) protein. However, whether such inhibition reduces the risk of coronary heart disease is not known. Human mutations that inactivate a gene encoding a drug target can mimic the action of an inhibitory drug and thus can be used to infer potential effects of that drug. Methods We sequenced the exons of NPC1L1 in 7364 patients with coronary heart disease and in 14,728 controls without such disease who were of European, African, or South Asian ancestry. We identified carriers of inactivating mutations (nonsense, splice-site, or frameshift mutations). In addition, we genotyped a specific inactivating mutation (p.Arg406X) in 22,590 patients with coronary heart disease and in 68,412 controls. We tested the association between the presence of an inactivating mutation and both plasma lipid levels and the risk of coronary heart disease. Results With sequencing, we identified 15 distinct NPC1L1 inactivating mutations; approximately 1 in every 650 persons was a heterozygous carrier for 1 of these mutations. Heterozygous carriers of NPC1L1 inactivating mutations had a mean LDL cholesterol level that was 12 mg per deciliter (0.31 mmol per liter) lower than that in noncarriers (P = 0.04). Carrier status was associated with a relative reduction of 53% in the risk of coronary heart disease (odds ratio for carriers, 0.47; 95% confidence interval, 0.25 to 0.87; P = 0.008). In total, only 11 of 29,954 patients with coronary heart disease had an inactivating mutation (carrier frequency, 0.04%) in contrast to 71 of 83,140 controls (carrier frequency, 0.09%). Conclusions Naturally occurring mutations that disrupt NPC1L1 function were found to be associated with reduced plasma LDL cholesterol levels and a reduced risk of coronary heart disease., National Human Genome Research Institute (U.S.) (Grant 5U54HG003067-11)

Observational and genetic studies have shown that lipoprotein(a) [Lp(a)] levels and apolipoprotein(a) [apo(a)] isoform size are both associated with coronary heart disease (CHD) risk, but the relative independence of these risk factors remains unclear. Clarification of this uncertainty is relevant to the potential of future Lp(a)-lowering therapies for the prevention of CHD. Methods: Plasma Lp(a) levels and apo(a) isoform size, estimated by the number of kringle IV (KIV) repeats, were measured in 995 patients with CHD and 998 control subjects. The associations between CHD risk and fifths of Lp(a) levels were assessed before and after adjustment for KIV repeats and, conversely, the associations between CHD risk and fifths of KIV repeats were assessed before and after adjustment for Lp(a) levels. Results: Individuals in the top fifth of Lp(a) levels had more than a twofold higher risk of CHD compared with those in the bottom fifth, and this association was materially unaltered after adjustment for KIV repeats [odds ratio (OR) 2.05, 95% confidence interval (CI) 1.38-3.04, P

Exome sequencing studies in complex diseases are challenged by the allelic heterogeneity, large number and modest effect sizes of associated variants on disease risk and the presence of large numbers of neutral variants, even in phenotypically relevant genes. Isolated populations with recent bottlenecks offer advantages for studying rare variants in complex diseases as they have deleterious variants that are present at higher frequencies as well as a substantial reduction in rare neutral variation. To explore the potential of the Finnish founder population for studying low-frequency (0.5–5%) variants in complex diseases, we compared exome sequence data on 3,000 Finns to the same number of non-Finnish Europeans and discovered that, despite having fewer variable sites overall, the average Finn has more low-frequency loss-of-function variants and complete gene knockouts. We then used several well-characterized Finnish population cohorts to study the phenotypic effects of 83 enriched loss-of-function variants across 60 phenotypes in 36,262 Finns. Using a deep set of quantitative traits collected on these cohorts, we show 5 associations (p, National Institutes of Health (U.S.) (NIH RC2 HL-102925)

Objective— Increased levels of lipoprotein(a) are a highly heritable risk factor for coronary artery disease (CAD). The genetic determinants of lipoprotein(a) levels are mainly because of genetic variation in the apolipoprotein(a) gene ( LPA ). We have tested the association of a relatively common null allele of LPA with lipoprotein(a) levels and CAD risk in a large case–control cohort. We have also examined how null allele genotyping complements apolipoprotein(a) isoform typing to refine the relationship between LPA isoform size and circulating lipoprotein(a) levels. Approach and Results— The LPA null allele (rs41272114) was genotyped in the PROCARDIS (Precocious Coronary Artery Disease) case–control cohort (4073 CAD cases and 4225 controls). Lipoprotein(a) levels were measured in 909 CAD cases and 922 controls; apolipoprotein(a) isoform size was estimated using sodium dodecyl sulfate–agarose gel electrophoresis and a high-throughput quantitative polymerase chain reaction–based method. Null carriers are common (null allele frequency, 3%) and have significantly lower circulating lipoprotein(a) levels ( P =2.1×10 −10 ) and reduced CAD risk (odds ratio, 0.79 [0.66–0.97]; P =0.023) compared with noncarriers. An additive allelic model of apolipoprotein(a) isoform size, refined by null allele genotype and quantitative polymerase chain reaction values, showed a sigmoid relationship with lipoprotein(a) levels, with baseline levels for longer isoform alleles and progressively higher levels of lipoprotein(a) for shorter isoform alleles. Conclusions— The LPA null allele (rs41272114) is associated with decreased circulating lipoprotein(a) levels and decreased CAD risk. Incorporating rs41272114 refined apolipoprotein(a) isoform size typing obtained by immunoblotting and quantitative polymerase chain reaction. A joint genomic and isoform analysis revealed details of the relationship between apolipoprotein(a) isoform size and circulating lipoprotein(a) level consistent with a threshold effect on lipoprotein secretion.

Objective: Increased levels of Lp(a) lipoprotein are a highly heritable risk factor for coronary artery disease (CAD). The genetic determinants of Lp(a) levels are mainly due to genetic variation in the apolipoprotein(a) gene (LPA). We have tested the association of a null allele of LPA with Lp(a) levels and CAD risk in a large case-control cohort. We have also examined how null allele genotyping complements apolipoprotein(a) isoform typing to refine the relationship between LPA isoform size and circulating Lp(a) levels. Approach and Results: The LPA null allele (rs41272114) was genotyped in the PROCARDIS case-control cohort (4,073 CAD cases, 4,225 controls). Lp(a) lipoprotein levels were measured in 909 CAD cases and 922 controls; apolipoprotein(a) isoform size was estimated using SDS-agarose gel electrophoresis and a high-throughput qPCR based method. Null carriers are common (null allele frequency 3%) and have significantly lower circulating Lp(a) levels (p=2.1x10-10) and reduced CAD risk (p=0.023) compared to non-carriers. An additive allelic model of apolipoprotein(a) isoform size, refined by null allele genotype and qPCR values, showed a sigmoid relationship with Lp(a) levels with baseline levels for longer isoform alleles and progressively higher levels of Lp(a) for shorter isoform alleles. Conclusions: The LPA null allele (rs41272444) is associated with decreased circulating Lp(a) levels and decreased CAD risk. A joint genomic and isoform analysis revealed details of the relationship between apolipoprotein(a) isoform size and circulating Lp(a) level consistent with a threshold effect on lipoprotein secretion.

HMIP-2 is a human quantitative trait locus affecting peripheral numbers, size and hemoglobin composition of red blood cells, with a marked effect on the persistence of the fetal form of hemoglobin, HbF, in adults. The locus consists of multiple common variants in an enhancer region for MYB (chr 6q23.3), which encodes the hematopoietic transcription factor cMYB. Studying a European population cohort and four African-descended groups of patients with sickle cell anemia, we found that all share a set of two spatially separate HbF-promoting alleles at HMIP-2, termed “A” and “B.” These typically occurred together (“A–B”) on European chromosomes, but existed on separate homologous chromosomes in Africans. Using haplotype signatures for “A” and “B,” we interrogated public population datasets. Haplotypes carrying only “A” or “B” were typical for populations in Sub-Saharan Africa. The “A–B” combination was frequent in European, Asian, and Amerindian populations. Both alleles were infrequent in tropical regions, possibly undergoing negative selection by geographical factors, as has been reported for malaria with other hematological traits. We propose that the ascertainment of worldwide distribution patterns for common, HbF-promoting alleles can aid their further genetic characterization, including the investigation of gene–environment interaction during human migration and adaptation.

Two distinct alleles in the gene encoding apolipoprotein L1 (APOL1), a major component of high-density lipoprotein, confer protection against Trypanosoma brucei rhodesiense infection and also increase risk for chronic kidney disease. Approximately 14% of Americans with African ancestry carry 2 APOL1 risk alleles, accounting for the high chronic kidney disease burden in this population.We tested whether APOL1 risk alleles significantly increase risk for atherosclerotic cardiovascular disease (CVD) in African Americans.We sequenced APOL1 in 1959 randomly selected African American participants in the Jackson Heart Study (JHS) and evaluated associations between APOL1 genotypes and renal and cardiovascular phenotypes. Previously identified association between APOL1 genotypes and chronic kidney disease was confirmed (P=2.4×10(-6)). Among JHS participants with 2 APOL1 risk alleles, we observed increased risk for CVD (50/763 events among participants without versus 37/280 events among participants with 2 risk alleles; odds ratio, 2.17; P=9.4×10(-4)). We replicated this novel association of APOL1 genotype with CVD in Women's Health Initiative (WHI) participants (66/292 events among participants without versus 37/101 events among participants with 2 risk alleles; odds ratio, 1.98; P=8.37×10(-3); JHS and WHI combined, P=8.5×10(-5); odds ratio, 2.12). The increased risk for CVD conferred by APOL1 alleles was robust to correction for both traditional CVD risk factors and chronic kidney disease.APOL1 variants contribute to atherosclerotic CVD risk, indicating a genetic component to cardiovascular health disparities in individuals of African ancestry. The considerable population of African Americans with 2 APOL1 risk alleles may benefit from intensive interventions to reduce CVD.

Background Plasma triglyceride levels are heritable and are correlated with the risk of coronary heart disease. Sequencing of the protein-coding regions of the human genome (the exome) has the potential to identify rare mutations that have a large effect on phenotype. Methods We sequenced the protein-coding regions of 18,666 genes in each of 3734 participants of European or African ancestry in the Exome Sequencing Project. We conducted tests to determine whether rare mutations in coding sequence, individually or in aggregate within a gene, were associated with plasma triglyceride levels. For mutations associated with triglyceride levels, we subsequently evaluated their association with the risk of coronary heart disease in 110,970 persons. Results An aggregate of rare mutations in the gene encoding apolipoprotein C3 (APOC3) was associated with lower plasma triglyceride levels. Among the four mutations that drove this result, three were loss-of-function mutations: a nonsense mutation (R19X) and two splice-site mutations (IVS2+1G -> A and IVS3+1G -> T). The fourth was a missense mutation (A43T). Approximately 1 in 150 persons in the study was a heterozygous carrier of at least one of these four mutations. Triglyceride levels in the carriers were 39% lower than levels in noncarriers (P

Although age-dependent effects on blood pressure (BP) have been reported, they have not been systematically investigated in large-scale genome-wide association studies (GWASs). We leveraged the infrastructure of three well-established consortia (CHARGE, GBPgen, and ICBP) and a nonstandard approach (age stratification and metaregression) to conduct a genome-wide search of common variants with age-dependent effects on systolic (SBP), diastolic (DBP), mean arterial (MAP), and pulse (PP) pressure. In a two-staged design using 99,241 individuals of European ancestry, we identified 20 genome-wide significant (p≤ 5 10) loci by using joint tests of the SNP main effect and SNP-age interaction. Nine of the significant loci demonstrated nominal evidence of age-dependent effects on BP by tests of the interactions alone. Index SNPs in the EHBP1L1 (DBP and MAP), CASZ1 (SBP and MAP), and GOSR2 (PP) loci exhibited the largest age interactions, with opposite directions of effect in the young versus the old. The changes in the genetic effects over time were small but nonnegligible (up to 1.58 mm Hg over 60 years). The EHBP1L1 locus was discovered through gene-age interactions only in whites but had DBP main effects replicated (p = 8.3 10) in 8,682 Asians from Singapore, indicating potential interethnic heterogeneity. A secondary analysis revealed 22 loci with evidence of age-specific effects (e.g., only in 20 to 29-year-olds). Age can be used to select samples with larger genetic effect sizes and more homogenous phenotypes, which may increase statistical power. Age-dependent effects identified through novel statistical approaches can provide insight into the biology and temporal regulation underlying BP associations. © 2014 The American Society of Human Genetics.

The majority of reported complex disease associations for common genetic variants have been identified through meta-analysis, a powerful approach that enables the use of large sample sizes while protecting against common artifacts due to population structure and repeated small-sample analyses sharing individual-level data. As the focus of genetic association studies shifts to rare variants, genes and other functional units are becoming the focus of analysis. Here we propose and evaluate new approaches for performing meta-analysis of rare variant association tests, including burden tests, weighted burden tests, variable-threshold tests and tests that allow variants with opposite effects to be grouped together. We show that our approach retains useful features from single-variant meta-analysis approaches and demonstrate its use in a study of blood lipid levels in ∼18,500 individuals genotyped with exome arrays. © 2014 Nature America, Inc.

The transforming growth factor beta 1 (TGF beta 1) signalling pathway is important in embryogenesis and has been implicated in hereditary haemorrhagic telangiectasia (HHT), atherosclerosis, tumorigenesis and immunomodulation. Therefore, identification of factors which modulate TGF beta 1 bioactivity in vivo is important. On a mixed genetic background, approximately 50% Tgfb1-/- conceptuses die midgestation from defective yolk sac vasculogenesis. The other half are developmentally normal but die three weeks postpartum. Intriguingly, the vascular defects of Tgfb1-/- mice share histological similarities to lesions seen in HHT patients. It has been suggested that dichotomy in Tgfb1-/- lethal phenotypes is due to maternal TGF beta 1 rescue of some, but not all, Tgfb1-/- embryos12. Here we show that the Tgfb1-/- phenotype depends on the genetic background of the conceptus. In NIH/Ola, C57BL/6J/Ola and F1 conceptuses, Tgfb1-/- lethality can be categorized into three developmental classes. A major codominant modifier gene of embryo lethality was mapped to proximal mouse chromosome 5, using a genome scan for non-mendelian distribution of alleles in Tgfb1-/- neonatal animals which survive prenatal lethality. This gene accounts for around three quarters of the genetic effect between mouse strains and can, in part, explain the distribution of the three lethal phenotypes. This approach, using neonatal DNA samples, is generally applicable to identification of loci that influence the effect of early embryonic lethal mutations, thus furthering knowledge of genetic interactions that occur during early mammalian development in vivo.

Genome-wide searches for susceptibility genes using pairs of affected siblings are being undertaken to dissect out individual polygenes that contribute to human multi-factorial diseases. Efficient identity-by-descent (IBD)-based sibpair linkage tests are available that test individual markers or maps of linked markers for linkage to a single putative susceptibility gene. In order to assess the support for linkage to a second putative susceptibility gene that happens to map close to an established susceptibility gene, it is necessary to use a method that correctly allows for the IBD distortion that directly results from the linkage between the two genes. A maximum likelihood-based, multilocus linkage test is proposed, which accounts for this interdependency and evaluates the support for an interaction between constituent susceptibility genes. The size and power of a test for a second linked susceptibility gene is investigated by simulation studies.

Objectives:\ud This study sought to investigate the role of secretory phospholipase A2 (sPLA2)-IIA in cardiovascular disease.\ud \ud Background:\ud Higher circulating levels of sPLA2-IIA mass or sPLA2 enzyme activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is causal. A recent phase III clinical trial of an sPLA2 inhibitor (varespladib) was stopped prematurely for lack of efficacy.\ud \ud Methods:\ud We conducted a Mendelian randomization meta-analysis of 19 general population studies (8,021 incident, 7,513 prevalent major vascular events [MVE] in 74,683 individuals) and 10 acute coronary syndrome (ACS) cohorts (2,520 recurrent MVE in 18,355 individuals) using rs11573156, a variant in PLA2G2A encoding the sPLA2-IIA isoenzyme, as an instrumental variable.\ud \ud Results:\ud PLA2G2A rs11573156 C allele associated with lower circulating sPLA2-IIA mass (38% to 44%) and sPLA2 enzyme activity (3% to 23%) per C allele. The odds ratio (OR) for MVE per rs11573156 C allele was 1.02 (95% confidence interval [CI]: 0.98 to 1.06) in general populations and 0.96 (95% CI: 0.90 to 1.03) in ACS cohorts. In the general population studies, the OR derived from the genetic instrumental variable analysis for MVE for a 1-log unit lower sPLA2-IIA mass was 1.04 (95% CI: 0.96 to 1.13), and differed from the non-genetic observational estimate (OR: 0.69; 95% CI: 0.61 to 0.79). In the ACS cohorts, both the genetic instrumental variable and observational ORs showed a null association with MVE. Instrumental variable analysis failed to show associations between sPLA2 enzyme activity and MVE.\ud \ud Conclusions:\ud Reducing sPLA2-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events.

Objective— Autosomal recessive hypercholesterolemia is a rare inherited disorder, characterized by extremely high total and low-density lipoprotein cholesterol levels, that has been previously linked to mutations in LDLRAP1 . We identified a family with autosomal recessive hypercholesterolemia not explained by mutations in LDLRAP1 or other genes known to cause monogenic hypercholesterolemia. The aim of this study was to identify the molecular pathogenesis of autosomal recessive hypercholesterolemia in this family. Approach and Results— We used exome sequencing to assess all protein-coding regions of the genome in 3 family members and identified a homozygous exon 8 splice junction mutation (c.894G>A, also known as E8SJM) in LIPA that segregated with the diagnosis of hypercholesterolemia. Because homozygosity for mutations in LIPA is known to cause cholesterol ester storage disease, we performed directed follow-up phenotyping by noninvasively measuring hepatic cholesterol content. We observed abnormal hepatic accumulation of cholesterol in the homozygote individuals, supporting the diagnosis of cholesterol ester storage disease. Given previous suggestions of cardiovascular disease risk in heterozygous LIPA mutation carriers, we genotyped E8SJM in >27 000 individuals and found no association with plasma lipid levels or risk of myocardial infarction, confirming a true recessive mode of inheritance. Conclusions— By integrating observations from Mendelian and population genetics along with directed clinical phenotyping, we diagnosed clinically unapparent cholesterol ester storage disease in the affected individuals from this kindred and addressed an outstanding question about risk of cardiovascular disease in LIPA E8SJM heterozygous carriers.

Angiotensin-I converting enzyme (ACE) occupies a pivotal role in cardiovascular homeostasis. Major loci for plasma ACE have been identified at ACE on Chromosome 17 and at ABO on Chromosome 9. We sought to characterise the genetic architecture of plasma ACE at finer resolution in two populations. We carried out a GWAS in 1810 individuals of Japanese ethnicity; this identified signals at ACE and ABO that together accounted for nearly half of the population variability of the trait. We conducted measured haplotype analysis at the ABO locus in 1425 members of 248 British families using haplotypes of three SNPs, which together tagged the alleles responsible for the principal blood group antigens A1, A2, B and O. Type O alleles were associated with intermediate plasma ACE activity compared to Type A1 alleles (in whom plasma ACE activity was ∼36% lower) and Type B alleles (in whom plasma ACE activity was ∼36% higher). We demonstrated heterogeneity among A alleles: A2 alleles were associated with plasma ACE activity that was very similar to the O alleles. Variation at ACE accounted for 35% of the trait variance, and variation at ABO accounted for 15%. A further 10% could be ascribed to polygenic effects.

Background— Association between the C677T polymorphism of the methylene tetrahydrofolate reductase ( MTHFR ) gene and congenital heart disease (CHD) is contentious. Methods and Results— We compared genotypes between CHD cases and controls and between mothers of CHD cases and controls. We placed our results in context by conducting meta-analyses of previously published studies. Among 5814 cases with primary genotype data and 10 056 controls, there was no evidence of association between MTHFR C677T genotype and CHD risk (odds ratio [OR], 0.96 [95% confidence interval, 0.87–1.07]). A random-effects meta-analysis of all studies (involving 7697 cases and 13 125 controls) suggested the presence of association (OR, 1.25 [95% confidence interval, 1.03–1.51]; P =0.022) but with substantial heterogeneity among contributing studies (I 2 =64.4%) and evidence of publication bias. Meta-analysis of large studies only (defined by a variance of the log OR 2 =0). Moreover, meta-analysis of 1781 mothers of CHD cases (829 of whom were genotyped in this study) and 19 861 controls revealed no evidence of association between maternal C677T genotype and risk of CHD in offspring (OR, 1.13 [95% confidence interval, 0.87–1.47]). There was no significant association between MTHFR genotype and CHD risk in large studies from regions with different levels of dietary folate. Conclusions— The MTHFR C677T polymorphism, which directly influences plasma folate levels, is not associated with CHD risk. Publication biases appear to substantially contaminate the literature with regard to this genetic association.

Contains fulltext : 128630.pdf (Publisher’s version ) (Open Access) Smoking influences body weight such that smokers weigh less than non-smokers and smoking cessation often leads to weight increase. The relationship between body weight and smoking is partly explained by the effect of nicotine on appetite and metabolism. However, the brain reward system is involved in the control of the intake of both food and tobacco. We evaluated the effect of single-nucleotide polymorphisms (SNPs) affecting body mass index (BMI) on smoking behavior, and tested the 32 SNPs identified in a meta-analysis for association with two smoking phenotypes, smoking initiation (SI) and the number of cigarettes smoked per day (CPD) in an Icelandic sample (N=34,216 smokers). Combined according to their effect on BMI, the SNPs correlate with both SI (r=0.019, P=0.00054) and CPD (r=0.032, P=8.0 x 10(-7)). These findings replicate in a second large data set (N=127,274, thereof 76,242 smokers) for both SI (P=1.2 x 10(-5)) and CPD (P=9.3 x 10(-5)). Notably, the variant most strongly associated with BMI (rs1558902-A in FTO) did not associate with smoking behavior. The association with smoking behavior is not due to the effect of the SNPs on BMI. Our results strongly point to a common biological basis of the regulation of our appetite for tobacco and food, and thus the vulnerability to nicotine addiction and obesity.

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. © 2013 Nature America, Inc. All rights reserved.

OBJECTIVE: End-stage coagulation and the structure/function of fibrin are implicated in the pathogenesis of ischemic stroke. We explored whether genetic variants associated with end-stage coagulation in healthy volunteers account for the genetic predisposition to ischemic stroke and examined their influence on stroke subtype.METHODS: Common genetic variants identified through genome-wide association studies of coagulation factors and fibrin structure/function in healthy twins (n = 2,100, Stage 1) were examined in ischemic stroke (n = 4,200 cases) using 2 independent samples of European ancestry (Stage 2). A third clinical collection having stroke subtyping (total 8,900 cases, 55,000 controls) was used for replication (Stage 3).RESULTS: Stage 1 identified 524 single nucleotide polymorphisms (SNPs) from 23 linkage disequilibrium blocks having significant association (p < 5 × 10(-8)) with 1 or more coagulation/fibrin phenotypes. The most striking associations included SNP rs5985 with factor XIII activity (p = 2.6 × 10(-186)), rs10665 with FVII (p = 2.4 × 10(-47)), and rs505922 in the ABO gene with both von Willebrand factor (p = 4.7 × 10(-57)) and factor VIII (p = 1.2 × 10(-36)). In Stage 2, the 23 independent SNPs were examined in stroke cases/noncases using MOnica Risk, Genetics, Archiving and Monograph (MORGAM) and Wellcome Trust Case Control Consortium 2 collections. SNP rs505922 was nominally associated with ischemic stroke (odds ratio = 0.94, 95% confidence interval = 0.88-0.99, p = 0.023). Independent replication in Meta-Stroke confirmed the rs505922 association with stroke, beta (standard error, SE) = 0.066 (0.02), p = 0.001, a finding specific to large-vessel and cardioembolic stroke (p = 0.001 and p = < 0.001, respectively) but not seen with small-vessel stroke (p = 0.811). INTERPRETATION: ABO gene variants are associated with large-vessel and cardioembolic stroke but not small-vessel disease. This work sheds light on the different pathogenic mechanisms underpinning stroke subtype.

Genome-wide scans for linkage of chromosome regions to type 1 diabetes in affected sib pair families have revealed that the major susceptibility locus resides within the major histocompatibility complex (MHC) on chromosome 6p21 (lambda S = 2.4). It is recognized that the MHC contains multiple susceptibility loci (referred to collectively as IDDM1), including the class II antigen receptor genes, which control the major pathological feature of the disease: T-lymphocyte-mediated autoimmune destruction of the insulin-producing pancreatic beta cells. However, the MHC genes, and a second locus, the insulin gene minisatellite on chromosome 11p15 (IDDM2; lambda S = 1.25), cannot account for all of the observed clustering of disease in families (lambda S = 15), and the scans suggested the presence of other susceptibility loci scattered throughout the genome. There are four additional loci for which there is currently sufficient evidence from linkage and association studies to justify fine mapping experiments: IDDM4 (FGF3/11q13), IDDM5 (ESR/6q22), IDDM8 (D6S281/6q27) and IDDM12 (CTLA-4/2q33). IDDM4, 5 and 8 were detected by genome scanning, and IDDM12 by a candidate gene strategy. Seven other named loci are not discounted but remain to be replicated widely. Multiple susceptibility loci were expected as genome-wide scans of the mouse model of type 1 diabetes had shown that although the MHC is the major mouse locus, at least 13 genes unlinked to the MHC are involved in the development of disease. Genome-wide scans using 1000 affected sibpair families will be required to be confident that all genes with effects on familial clustering equivalent to the insulin gene locus (lambda S = 1.25) have been detected. The identification of aetiological determinants requires exclusion of hitchhiking polymorphisms in regions of linkage disequilibrium, as demonstrated for the MHC and the insulin gene loci, and functional studies implicating the disease-associated variant in pathogenesis. Ultimately, targeting of specific candidate mutations in mice by homologous recombination and replacement will be necessary to prove the primary role of any candidate mutation.

SUMMARY The Maximum Lod Score method for affected relative-pair analysis, introduced by Risch, is a powerful method for detecting linkage between an autosomal marker locus and disease. In order to use the method to detect linkage to markers on the X-chromosome, some modification is necessary. Here we extend the method to be applicable to X-chromosomal data, and derive genetic restrictions on the haplotype-sharing probabilities analogous to the ‘possible triangle’ restrictions described by Holmans for the autosomal case. Size criteria are derived using asymptotic theory and simulation, and the power is calculated for a number of possible underlying models. The method is applied to data from 284 type 1 diabetic families and evidence is found for the presence of one or more diabetogenic loci on the X-chromosome.

The renin-angiotensin system regulates blood pressure and sodium balance. The angiotensinogen gene which encodes the key substrate within this system has been linked to essential hypertension in White Europeans. It has been suggested that people of West African ancestry may have a different genetic basis for hypertension. In this study we have tested whether there is linkage of the angiotensinogen gene to essential hypertension in African Caribbeans from St. Vincent and the Grenadines. DNA from 63 affected sibling pairs with hypertension was tested for linkage by analyzing whether there was excess allele sharing among siblings genotyped using an angiotensinogen dinucleotide repeat sequence. There was significant support for linkage (T = 3.07, P = 0.001) and association of this locus to hypertension (chi 2 = 50.2, 12 degrees of freedom, P << 0.001). A DNA polymorphism which alters methionine to threonine at position 235 (M235T) within the angiotensinogen peptide has been associated previously with hypertension. However, we found no association of this variant with hypertension in this study. These findings provide support for linkage and association of the angiotensinogen locus to hypertension in African Caribbeans and suggest some similarities in the genetic basis of essential hypertension in populations of different ethnicity.

We carried out a genome-wide association study (GWAS) of congenital heart disease (CHD). Our discovery cohort comprised 1,995 CHD cases and 5,159 controls and included affected individuals from each of the 3 major clinical CHD categories (with septal, obstructive and cyanotic defects). When all CHD phenotypes were considered together, no region achieved genome-wide significant association. However, a region on chromosome 4p16, adjacent to the MSX1 and STX18 genes, was associated (P = 9.5 × 10 -7) with the risk of ostium secundum atrial septal defect (ASD) in the discovery cohort (N = 340 cases), and this association was replicated in a further 417 ASD cases and 2,520 controls (replication P = 5.0 × 10 -5; odds ratio (OR) in replication cohort = 1.40, 95% confidence interval (CI) = 1.19-1.65; combined P = 2.6 × 10 -10). Genotype accounted for ∼9% of the population-attributable risk of ASD. © 2013 Nature America, Inc. All rights reserved.

The locus encompassing the corticosteroidogenic genes CYP11B2 and CYP11B1 is of potential importance in essential hypertension. We analyzed the association of polymorphisms at this locus with risk of essential hypertension, using 2 white case–control collections for discovery (n=3340) and confirmation (n=2929). Single-marker and haplotype analyses were performed, with the CYP11B2 Intron 2 Conversion polymorphism showing strongest association with hypertension in both cohorts and in combined analysis (odds ratio=1.16, P =8.54×10 −5 ). The CYP11B1 ACA haplotype associated with increased risk of hypertension relative to the alternative, GTC (odds ratio=1.11; P =7.4×10 −3 ), whereas the CYP11B2 TWtC haplotype seemed protective relative to the contrasting CConvT (odds ratio=0.88, P =2.2×10 −3 ). Analysis spanning the whole CYP11B1/CYP11B2 locus showed that haplotypes associated with raised risk of hypertension tend to coexist. Functional analysis of heterozygous human adrenal tissue demonstrated decreased CYP11B2 expression and increased CYP11B1 expression for those alleles associating with reduced risk of hypertension. These results confirm the hypertensive influence of this locus, with data suggesting a complex digenic mechanism whereby altered relative CYP11B1 and CYP11B2 gene expression could have a chronic effect on enzyme activity and corticosteroid synthesis.

Seuls les auteurs INRA et les 100 premiers auteurs figurent sur la notice. Group Authors : DIAbet Genetics Replication traits and provide insight into the underlying biological pathways La liste complète des auteurs et de leurs affiliations des auteurs est disponible sur la publication, p. 1004-1005, à l'adresse suivante : https://www.nature.com/articles/ng.2385.pdf; International audience; Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.

The manifestation of coronary artery disease (CAD) follows a well-choreographed series of events that includes damage of arterial endothelial cells and deposition of lipids in the sub-endothelial layers. Genome-wide association studies (GWAS) of multiple populations with distinctive genetic and lifestyle backgrounds are a crucial step in understanding global CAD pathophysiology. In this study, we report a GWAS on the genetic basis of arterial stenosis as measured by cardiac catheterization in a Lebanese population. The locus of the phosphatase and actin regulator 1 gene (PHACTR1) showed association with coronary stenosis in a discovery experiment with genome wide data in 1,949 individuals (rs9349379, OR = 1.37, p = 1.57×10(-5)). The association was replicated in an additional 2,547 individuals (OR = 1.31, p = 8.85×10(-6)), leading to genome-wide significant association in a combined analysis (OR = 1.34, p = 8.02×10(-10)). Results from this GWAS support a central role of PHACTR1 in CAD susceptibility irrespective of lifestyle and ethnic divergences. This association provides a plausible component for understanding molecular mechanisms involved in the formation of stenosis in cardiac vessels and a potential drug target against CAD.

Background— Carotid intima-media thickness (cIMT) is a widely accepted marker of subclinical atherosclerosis. To date, large-scale investigations of genetic determinants of cIMT are sparse. Methods and Results— To identify cIMT-associated genes and genetic variants, a discovery analysis using the Illumina 200K CardioMetabochip was conducted in 3430 subjects with detailed ultrasonographic determinations of cIMT from the IMPROVE (Carotid Intima Media Thickness [IMT] and IMT-Progression as Predictors of Vascular Events in a High Risk European Population) study. Segment-specific IMT measurements of common carotid, bifurcation, and internal carotid arteries, and composite IMT variables considering the whole carotid tree (IMT mean , IMT max , and IMT mean-max ), were analyzed. A replication stage investigating 42 single-nucleotide polymorphisms for association with common carotid IMT was undertaken in 5 independent European cohorts (total n=11 590). A locus on chromosome 16 (lead single-nucleotide polymorphism rs4888378, intronic in CFDP1 ) was associated with cIMT at significance levels passing multiple testing correction at both stages (array-wide significant discovery P =6.75×10 −7 for IMT max ; replication P =7.24×10 −6 for common cIMT; adjustments for sex, age, and population substructure where applicable; minor allele frequency 0.43 and 0.41, respectively). The protective minor allele was associated with lower carotid plaque score in a replication cohort ( P =0.04, n=2120) and lower coronary artery disease risk in 2 case-control studies of subjects with European ancestry (odds ratio [95% confidence interval] 0.83 [0.77–0.90], P =6.53×10 −6 , n=13 591; and 0.95 [0.92–0.98], P =1.83×10 −4 , n=82 297, respectively). Queries of human biobank data sets revealed associations of rs4888378 with nearby gene expression in vascular tissues (n=126–138). Conclusions— This study identified rs4888378 in the BCAR1-CFDP1-TMEM170A locus as a novel genetic determinant of cIMT and coronary artery disease risk in individuals of European descent.