Genome-wide association study identifies TNFSF13 as a susceptibility gene for IgA in a South Chinese population in smokers

IgA is an important factor in our immune system. There are many diseases associated with it, such as IgA nephropathy, IgA deficiency, and so on. In order to describe the relationship between the genes and the IgA level, we performed a genome-wide association study of serum IgA with 1,999 healthy Chinese men in the first stage and replicated on an independent Chinese sample with 1,496 subjects in the second stage. Association between each SNP with IgA was estimated by multivariate linear regression analysis conditioned on age and smoke. Haplotype analysis for the block around the top SNP was performed. In the first stage, one genomic locus was identified to be significantly associated with IgA. The loci is TNFSF13 (17p13.1; rs3803800; P?=?6.26?×?10(-8)). In smoke-specific analysis, rs3803800 was approximately significantly associated with IgA levels in smokers (P?=?3.96?×?10(-7)), while no association was observed in nonsmokers (P?=?2.28?×?10(-1)). In addition, we performed the haplotype analysis on chromosome 17 with the SNPs around rs3803800. Although the total P value for the haplotype did not acquire significant difference, three haplotypes (TGAG, CACG, and CACA) reached significant (P?相似文献   

Identification of a systemic lupus erythematosus susceptibility locus at 11p13 between PDHX and CD44 in a multiethnic study

Systemic lupus erythematosus (SLE) is considered to be the prototypic autoimmune disease, with a complex genetic architecture influenced by environmental factors. We sought to replicate a putative association at 11p13 not yet exceeding genome-wide significance (p < 5 × 10(-8)) identified in a genome-wide association study (GWAS). Our GWA scan identified two intergenic SNPs located between PDHX and CD44 showing suggestive evidence of association with SLE in cases of European descent (rs2732552, p = 0.004, odds ratio [OR] = 0.78; rs387619, p = 0.003, OR = 0.78). The replication cohort consisted of >15,000 subjects, including 3562 SLE cases and 3491 controls of European ancestry, 1527 cases and 1811 controls of African American (AA) descent, and 1265 cases and 1260 controls of Asian origin. We observed robust association at both rs2732552 (p = 9.03 × 10(-8), OR = 0.83) and rs387619 (p = 7.7 × 10(-7), OR = 0.83) in the European samples with p(meta) = 1.82 × 10(-9) for rs2732552. The AA and Asian SLE cases also demonstrated association at rs2732552 (p = 5 × 10(-3), OR = 0.81 and p = 4.3 × 10(-4), OR = 0.80, respectively). A meta-analysis of rs2732552 for all racial and ethnic groups studied produced p(meta) = 2.36 × 10(-13). This locus contains multiple regulatory sites that could potentially affect expression and functions of CD44, a cell-surface glycoprotein influencing immunologic, inflammatory, and oncologic phenotypes, or PDHX, a subunit of the pyruvate dehydrogenase complex.     

WNT16 influences bone mineral density, cortical bone thickness, bone strength, and osteoporotic fracture risk

We aimed to identify genetic variants associated with cortical bone thickness (CBT) and bone mineral density (BMD) by performing two separate genome-wide association study (GWAS) meta-analyses for CBT in 3 cohorts comprising 5,878 European subjects and for BMD in 5 cohorts comprising 5,672 individuals. We then assessed selected single-nucleotide polymorphisms (SNPs) for osteoporotic fracture in 2,023 cases and 3,740 controls. Association with CBT and forearm BMD was tested for ～2.5 million SNPs in each cohort separately, and results were meta-analyzed using fixed effect meta-analysis. We identified a missense SNP (Thr>Ile; rs2707466) located in the WNT16 gene (7q31), associated with CBT (effect size of -0.11 standard deviations [SD] per C allele, P = 6.2 × 10(-9)). This SNP, as well as another nonsynonymous SNP rs2908004 (Gly>Arg), also had genome-wide significant association with forearm BMD (-0.14 SD per C allele, P = 2.3 × 10(-12), and -0.16 SD per G allele, P = 1.2 × 10(-15), respectively). Four genome-wide significant SNPs arising from BMD meta-analysis were tested for association with forearm fracture. SNP rs7776725 in FAM3C, a gene adjacent to WNT16, was associated with a genome-wide significant increased risk of forearm fracture (OR = 1.33, P = 7.3 × 10(-9)), with genome-wide suggestive signals from the two missense variants in WNT16 (rs2908004: OR = 1.22, P = 4.9 × 10(-6) and rs2707466: OR = 1.22, P = 7.2 × 10(-6)). We next generated a homozygous mouse with targeted disruption of Wnt16. Female Wnt16(-/-) mice had 27% (P<0.001) thinner cortical bones at the femur midshaft, and bone strength measures were reduced between 43%-61% (6.5 × 10(-13)相似文献   

Are bone mineral density loci associated with hip osteoporotic fractures? A validation study on previously reported genome-wide association loci in a Chinese population

Osteoporosis is a heritable disease characterized mainly by low bone mineral density (BMD) and/or osteoporotic fractures (OF). Most genome-wide association studies on osteoporosis have focused on BMD, whereas little effort has been expended to identify genetic variants directly linked to OF. To determine whether BMD-loci are also associated with OF risk, we performed a validation study to examine 23 BMD-loci reported by recent genome-wide association studies for association with hip OF risk. Our sample consisted of 700 elderly Chinese Han subjects, 350 with hip OF and 350 healthy matched controls. We identified four BMD-loci that were significantly associated with hip OF in this Chinese population, including 7q21 (FLJ42280, P = 1.17 × 10(-4) for rs4729260; P = 0.008 for rs7781370), 6p21 (MHC, P = 0.004 for rs3130340), 13q14 (TNFSF11, P = 0.012 for rs9533090; P = 0.018 for rs9594759; P = 0.020 for rs9594738; P = 0.044 for rs9594751), and 18q21 (TNFRSF11A, P = 0.015 for rs884205). The SNP rs4729260 at 7q21 remained significantly associated, even after conservative Bonferroni's correction. Our results further highlight the importance of these loci in the pathogenesis of osteoporosis, and demonstrate that it is feasible and useful to use OF as the direct phenotype to conduct genetic studies, to enhance our understanding of the genetic architecture of osteoporosis.     

Use of a multiethnic approach to identify rheumatoid- arthritis-susceptibility loci, 1p36 and 17q12

We have previously shown that rheumatoid arthritis (RA) risk alleles overlap between different ethnic groups. Here, we utilize a multiethnic approach to show that we can effectively discover RA risk alleles. Thirteen putatively associated SNPs that had not yet exceeded genome-wide significance (p < 5 × 10(-8)) in our previous RA genome-wide association study (GWAS) were analyzed in independent sample sets consisting of 4,366 cases and 17,765 controls of European, African American, and East Asian ancestry. Additionally, we conducted an overall association test across all 65,833 samples (a GWAS meta-analysis plus the replication samples). Of the 13 SNPs investigated, four were significantly below the study-wide Bonferroni corrected p value threshold (p < 0.0038) in the replication samples. Two SNPs (rs3890745 at the 1p36 locus [p = 2.3 × 10(-12)] and rs2872507 at the 17q12 locus [p = 1.7 × 10(-9)]) surpassed genome-wide significance in all 16,659 RA cases and 49,174 controls combined. We used available GWAS data to fine map these two loci in Europeans and East Asians, and we found that the same allele conferred risk in both ethnic groups. A series of bioinformatic analyses identified TNFRSF14-MMEL1 at the 1p36 locus and IKZF3-ORMDL3-GSDMB at the 17q12 locus as the genes most likely associated with RA. These findings demonstrate empirically that a multiethnic approach is an effective strategy for discovering RA risk loci, and they suggest that combining GWASs across ethnic groups represents an efficient strategy for gaining statistical power.     

Associations between single nucleotide polymorphisms in iron-related genes and iron status in multiethnic populations

The existence of multiple inherited disorders of iron metabolism suggests genetic contributions to iron deficiency. We previously performed a genome-wide association study of iron-related single nucleotide polymorphisms (SNPs) using DNA from white men aged ≥ 25 y and women ≥ 50 y in the Hemochromatosis and Iron Overload Screening (HEIRS) Study with serum ferritin (SF) ≤ 12 μg/L (cases) and controls (SF >100 μg/L in men, SF >50 μg/L in women). We report a follow-up study of white, African-American, Hispanic, and Asian HEIRS participants, analyzed for association between SNPs and eight iron-related outcomes. Three chromosomal regions showed association across multiple populations, including SNPs in the TF and TMPRSS6 genes, and on chromosome 18q21. A novel SNP rs1421312 in TMPRSS6 was associated with serum iron in whites (p = 3.7 × 10(-6)) and replicated in African Americans (p = 0.0012).Twenty SNPs in the TF gene region were associated with total iron-binding capacity in whites (p<4.4 × 10(-5)); six SNPs replicated in other ethnicities (p<0.01). SNP rs10904850 in the CUBN gene on 10p13 was associated with serum iron in African Americans (P = 1.0 × 10(-5)). These results confirm known associations with iron measures and give unique evidence of their role in different ethnicities, suggesting origins in a common founder.     

Four novel Loci (19q13, 6q24, 12q24, and 5q14) influence the microcirculation in vivo

There is increasing evidence that the microcirculation plays an important role in the pathogenesis of cardiovascular diseases. Changes in retinal vascular caliber reflect early microvascular disease and predict incident cardiovascular events. We performed a genome-wide association study to identify genetic variants associated with retinal vascular caliber. We analyzed data from four population-based discovery cohorts with 15,358 unrelated Caucasian individuals, who are members of the Cohort for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and replicated findings in four independent Caucasian cohorts (n = 6,652). All participants had retinal photography and retinal arteriolar and venular caliber measured from computer software. In the discovery cohorts, 179 single nucleotide polymorphisms (SNP) spread across five loci were significantly associated (p<5.0×10(-8)) with retinal venular caliber, but none showed association with arteriolar caliber. Collectively, these five loci explain 1.0%-3.2% of the variation in retinal venular caliber. Four out of these five loci were confirmed in independent replication samples. In the combined analyses, the top SNPs at each locus were: rs2287921 (19q13; p = 1.61×10(-25), within the RASIP1 locus), rs225717 (6q24; p?=?1.25×10(-16), adjacent to the VTA1 and NMBR loci), rs10774625 (12q24; p = 2.15×10(-13), in the region of ATXN2,SH2B3 and PTPN11 loci), and rs17421627 (5q14; p?=?7.32×10(-16), adjacent to the MEF2C locus). In two independent samples, locus 12q24 was also associated with coronary heart disease and hypertension. Our population-based genome-wide association study demonstrates four novel loci associated with retinal venular caliber, an endophenotype of the microcirculation associated with clinical cardiovascular disease. These data provide further insights into the contribution and biological mechanisms of microcirculatory changes that underlie cardiovascular disease.     

Genetic variant in TP63 on locus 3q28 is associated with risk of lung adenocarcinoma among never-smoking females in Asia

A recent genome-wide association study (GWAS) of subjects from Japan and South Korea reported a novel association between the TP63 locus on chromosome 3q28 and risk of lung adenocarcinoma (p = 7.3 × 10(-12)); however, this association did not achieve genome-wide significance (p ≤ 10(-7)) among never-smoking males or females. To determine if this association with lung cancer risk is independent of tobacco use, we genotyped the TP63 SNPs reported by the previous GWAS (rs10937405 and rs4488809) in 3,467 never-smoking female lung cancer cases and 3,787 never-smoking female controls from 10 studies conducted in Taiwan, Mainland China, South Korea, and Singapore. Genetic variation in rs10937405 was associated with risk of lung adenocarcinoma [n = 2,529 cases; p = 7.1 × 10(-8); allelic risk = 0.80, 95% confidence interval (CI) = 0.74-0.87]. There was also evidence of association with squamous cell carcinoma of the lung (n = 302 cases; p = 0.037; allelic risk = 0.82, 95% CI = 0.67-0.99). Our findings provide strong evidence that genetic variation in TP63 is associated with the risk of lung adenocarcinoma among Asian females in the absence of tobacco smoking.     

PHACTR3基因与中国汉族和美国高加索人群骨密度的关联研究

研究组前期的全基因组关联研究发现PHACTR3基因与骨折关联,为了检测该基因与骨密度的关联关系,采用精细定位关联研究来检测PHACTR3基因内及其附近的SNPs与骨密度的关系。首先在中国样本（1627个不相关的汉族样本）和美国样本（2286个不相关高加索样本）中对PHACTR3基因的140个SNPs进行基因分型,然后采用Plink软件检测PHACTR3基因与腰椎和髋部骨密度的关联关系。发现研究组以前报道的与骨折关联的SNPs rs1555364和rs6064822与腰椎和髋部骨密度关联（P=4．89×10^-2-1．26×10^-2）。另外还发现位于PHACTR3基因内含子中3个SNPs位点（rs6027138,rs1182531和rs1182532）与中国人群和白人腰椎骨密度均显著关联,将中国人与白人样本合并起来进行荟萃分析（Meta—analysis）,得到合并P值为1．40×10^-3到4．00×10^-4,另外发现rs6064820与髋部BMD相关联,合并P值为6．70×10^-3。本研究进一步证实了PHACTR3基因在骨密度变异中的作用,对骨质疏松发病机制的认识提供了新的理论依据。     

Effects of genetic variants on lipid parameters and dyslipidemia in a Chinese population

A number of recent genome-wide association (GWA) studies have identified several novel genetic determinants of plasma lipid and lipoprotein concentrations in European populations. However, it is still unclear whether these loci identified in Caucasian GWA studies also exert the same effect on lipid and lipoprotein concentrations in a Chinese population. We genotyped 10 single-nucleotide polymorphisms (SNPs) in nine loci in a Chinese Han population sample (n = 4,192) and assessed the associations of these SNPs with metabolic traits, using linear regression adjusted for age, gender, diabetes status, and body mass index. Three variants (rs12654264, P ～ 1.7 × 10(-6); rs3764261, P ～ 7.1 × 10(-7); and rs4420638, P ～ 1.1 × 10(-3)) showed strong evidence for association with total cholesterol; four variants (rs780094, P ～ 1.8 × 10(-11); rs17145738, P ～ 5.0 × 10(-7); rs326, P ～ 2.3 × 10(-6); and rs439401, P ～ 2.2 × 10(-5)) showed strong evidence for association with triglycerides, four variants (rs17145738, P ～ 1.9 × 10(-4); rs326, P ～ 9.7 × 10(-4); rs1800588, P ～ 1.5 × 10(-7); and rs3764261, P ～ 4.3 × 10(-14)) showed strong evidence for association with HDL-cholesterol (HDL-C), two variants (rs12654264, P ～ 2.3 × 10(-5); and rs4420638, P ～ 3.6 × 10(-4)) showed strong evidence for association with LDL-C, and four variants (rs326, P ～ 2.8 × 10(-3); rs1800588, P ～ 6.1 × 10(-4); rs3764261, P ～ 2.0 × 10(-3); and rs4420638, P ～ 9.4 × 10(-5)) showed strong evidence for association with total cholesterol-HDL-C-related ratio. These SNPs generated strong combined effects on lipid traits and dyslipidemia. Our findings indicate that the variants that associated with metabolic traits in Europeans may also play a role in a Chinese Han population.     

Large-scale genome-wide association study of Asian population reveals genetic factors in FRMD4A and other loci influencing smoking initiation and nicotine dependence

Diseases related to smoking are the second leading cause of death in the world. Cigarette smoking is a risk factor for several diseases such as cancer and cardiovascular and respiratory disorders. Despite increasing evidence of genetic determination, the susceptibility genes and loci underlying various aspects of smoking behavior are largely unknown. Moreover, almost all reported genome-wide association studies (GWASs) have been performed on samples of European origin, limiting the applicability of the results to other ethnic populations. In this first GWAS on smoking behavior in an Asian population, after analyzing 8,842 DNA samples from the Korea Association Resource project with 352,228 single nucleotide polymorphisms (SNPs) genotyped for each sample, we identified 8 SNPs significantly associated with smoking initiation (SI) and 4 with nicotine dependence (ND). Because of the current unavailability of an independent Asian smoking sample, we replicated the discoveries in independent samples of European-American and African-American origin. Of the 12 SNPs examined in the replicated samples, we identified two SNPs, in the regulator of G-protein signaling 17 gene (rs7747583, p value(meta)?=?6.40?×?10(-6); rs2349433, p value(meta)?=?5.57?×?10(-6)), associated with SI. Also, we found two SNPs significantly associated with ND; one in the FERM domain containing 4A (rs4424567, p value(meta)?=?2.30?×?10(-6)) and the other at 7q31.1 (rs848353, p value(meta)?=?9.16?×?10(-8)). These SNPs represent novel targets for examination of smoking behavior and warrant further investigation using independent samples.     

Genome-Wide Scan Identifies Variant in TNFSF13 Associated with Serum IgM in a Healthy Chinese Male Population

IgM provides a first line of defense during microbial infections. Serum IgM levels are detected routinely in clinical practice. And IgM is a genetically complex trait. We conducted a two-stage genome-wide association study (GWAS) to identify genetic variants affecting serum IgM levels in a Chinese population of 3495, including 1999 unrelated subjects in the first stage and 1496 independent individuals in the second stage. Our data show that a common single nucleotide polymorphism (SNP), rs11552708 located in the TNFSF13 gene was significantly associated with IgM levels (p = 5.00×10⁻⁷ in first stage, p = 1.34×10⁻³ in second stage, and p = 4.22×10⁻⁹ when combined). Besides, smoking was identified to be associated with IgM levels in both stages (P<0.05), but there was no significant interaction between smoking and the identified SNP (P>0.05). It is suggested that TNFSF13 may be a susceptibility gene affecting serum IgM levels in Chinese male population.     

Genome-wide association study confirming association of HLA-DP with protection against chronic hepatitis B and viral clearance in Japanese and Korean

Hepatitis B virus (HBV) infection can lead to serious liver diseases, including liver cirrhosis (LC) and hepatocellular carcinoma (HCC); however, about 85-90% of infected individuals become inactive carriers with sustained biochemical remission and very low risk of LC or HCC. To identify host genetic factors contributing to HBV clearance, we conducted genome-wide association studies (GWAS) and replication analysis using samples from HBV carriers and spontaneously HBV-resolved Japanese and Korean individuals. Association analysis in the Japanese and Korean data identified the HLA-DPA1 and HLA-DPB1 genes with P(meta)?=?1.89×10?12 for rs3077 and P(meta)?=?9.69×10?1? for rs9277542. We also found that the HLA-DPA1 and HLA-DPB1 genes were significantly associated with protective effects against chronic hepatitis B (CHB) in Japanese, Korean and other Asian populations, including Chinese and Thai individuals (P(meta)?=?4.40×10?1? for rs3077 and P(meta)?=?1.28×10?1? for rs9277542). These results suggest that the associations between the HLA-DP locus and the protective effects against persistent HBV infection and with clearance of HBV were replicated widely in East Asian populations; however, there are no reports of GWAS in Caucasian or African populations. Based on the GWAS in this study, there were no significant SNPs associated with HCC development. To clarify the pathogenesis of CHB and the mechanisms of HBV clearance, further studies are necessary, including functional analyses of the HLA-DP molecule.     

Genome-wide association study identifies a single major locus contributing to survival into old age; the APOE locus revisited

By studying the loci that contribute to human longevity, we aim to identify mechanisms that contribute to healthy aging. To identify such loci, we performed a genome-wide association study (GWAS) comparing 403 unrelated nonagenarians from long-living families included in the Leiden Longevity Study (LLS) and 1670 younger population controls. The strongest candidate SNPs from this GWAS have been analyzed in a meta-analysis of nonagenarian cases from the Rotterdam Study, Leiden 85-plus study, and Danish 1905 cohort. Only one of the 62 prioritized SNPs from the GWAS analysis (P<1×10(-4) ) showed genome-wide significance with survival into old age in the meta-analysis of 4149 nonagenarian cases and 7582 younger controls [OR=0.71 (95% CI 0.65-0.77), P=3.39 × 10(-17) ]. This SNP, rs2075650, is located in TOMM40 at chromosome 19q13.32 close to the apolipoprotein E (APOE) gene. Although there was only moderate linkage disequilibrium between rs2075650 and the ApoE ε4 defining SNP rs429358, we could not find an APOE-independent effect of rs2075650 on longevity, either in cross-sectional or in longitudinal analyses. As expected, rs429358 associated with metabolic phenotypes in the offspring of the nonagenarian cases from the LLS and their partners. In addition, we observed a novel association between this locus and serum levels of IGF-1 in women (P=0.005). In conclusion, the major locus determining familial longevity up to high age as detected by GWAS was marked by rs2075650, which tags the deleterious effects of the ApoE ε4 allele. No other major longevity locus was found.     

Genome-wide association study of genetic determinants of LDL-c response to atorvastatin therapy: importance of Lp(a)

We carried out a genome-wide association study (GWAS) of LDL-c response to statin using data from participants in the Collaborative Atorvastatin Diabetes Study (CARDS; n = 1,156), the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT; n = 895), and the observational phase of ASCOT (n = 651), all of whom were prescribed atorvastatin 10 mg. Following genome-wide imputation, we combined data from the three studies in a meta-analysis. We found associations of LDL-c response to atorvastatin that reached genome-wide significance at rs10455872 (P = 6.13 × 10(-9)) within the LPA gene and at two single nucleotide polymorphisms (SNP) within the APOE region (rs445925; P = 2.22 × 10(-16) and rs4420638; P = 1.01 × 10(-11)) that are proxies for the ε2 and ε4 variants, respectively, in APOE. The novel association with the LPA SNP was replicated in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial (P = 0.009). Using CARDS data, we further showed that atorvastatin therapy did not alter lipoprotein(a) [Lp(a)] and that Lp(a) levels accounted for all of the associations of SNPs in the LPA gene and the apparent LDL-c response levels. However, statin therapy had a similar effect in reducing cardiovascular disease (CVD) in patients in the top quartile for serum Lp(a) levels (HR = 0.60) compared with those in the lower three quartiles (HR = 0.66; P = 0.8 for interaction). The data emphasize that high Lp(a) levels affect the measurement of LDL-c and the clinical estimation of LDL-c response. Therefore, an apparently lower LDL-c response to statin therapy may indicate a need for measurement of Lp(a). However, statin therapy seems beneficial even in those with high Lp(a).     

Genome-wide association study on bipolar disorder in the Bulgarian population

Bipolar disorder is a severe psychiatric disorder influenced by environmental and genetic factors. Genetic studies have implicated many variants in the disease's etiology but only few have been successfully replicated. We conducted a genome-wide association study (GWAS) on bipolar disorder in the Bulgarian population followed by a replication study of the top 100 single nucleotide polymorphisms (SNPs) showing the smallest P values. The GWAS was performed on 188 bipolar disorder patients and 376 control subjects genotyped on the Illumina 550 platform. The replication study was conducted on 122 patients and 328 controls. Although our study did not show any association P value that achieved genome-wide significance, and none of the top 100 SNPs reached the Bonferroni-corrected P value in the replication study, the plausible involvement of some variants cannot be entirely discarded. Three polymorphisms, rs8099939 [P = 2.12 × 10(-6), odds ratio (OR) = 1.95, 95% confidence interval (CI) = 1.43-2.67] in GRIK5, rs6122972 (P = 3.11 × 10(-6), OR = 2.02, 95% CI = 1.46-2.80) in PARD6B and rs2289700 (P = 9.14 × 10(-6), OR = 2.13, 95% CI = 1.53-2.95) in CTSH remained associated at a similar level after Mantel-Haenszel test for combining the results from the genome-wide and replication studies. A modest association was also detected for SNP rs1012053 (GWAS P = 4.50 × 10(-2)) in DGKH, which has already been reported as the most significant variant in a previous genome-wide scan on bipolar disorder. However, further studies using larger datasets are needed to identify variants with smaller effects that contribute to the risk of bipolar disorder.     

Multiple common susceptibility variants near BMP pathway loci GREM1, BMP4, and BMP2 explain part of the missing heritability of colorectal cancer

Genome-wide association studies (GWAS) have identified 14 tagging single nucleotide polymorphisms (tagSNPs) that are associated with the risk of colorectal cancer (CRC), and several of these tagSNPs are near bone morphogenetic protein (BMP) pathway loci. The penalty of multiple testing implicit in GWAS increases the attraction of complementary approaches for disease gene discovery, including candidate gene- or pathway-based analyses. The strongest candidate loci for additional predisposition SNPs are arguably those already known both to have functional relevance and to be involved in disease risk. To investigate this proposition, we searched for novel CRC susceptibility variants close to the BMP pathway genes GREM1 (15q13.3), BMP4 (14q22.2), and BMP2 (20p12.3) using sample sets totalling 24,910 CRC cases and 26,275 controls. We identified new, independent CRC predisposition SNPs close to BMP4 (rs1957636, P = 3.93×10(-10)) and BMP2 (rs4813802, P = 4.65×10(-11)). Near GREM1, we found using fine-mapping that the previously-identified association between tagSNP rs4779584 and CRC actually resulted from two independent signals represented by rs16969681 (P = 5.33×10(-8)) and rs11632715 (P = 2.30×10(-10)). As low-penetrance predisposition variants become harder to identify-owing to small effect sizes and/or low risk allele frequencies-approaches based on informed candidate gene selection may become increasingly attractive. Our data emphasise that genetic fine-mapping studies can deconvolute associations that have arisen owing to independent correlation of a tagSNP with more than one functional SNP, thus explaining some of the apparently missing heritability of common diseases.     

Genome-wide association study of treatment refractory schizophrenia in Han Chinese

We report the first genome-wide association study of a joint analysis using 795 Han Chinese individuals with treatment-refractory schizophrenia (TRS) and 806 controls. Three loci showed suggestive significant association with TRS were identified. These loci include: rs10218843 (P = 3.04 × 10(-7)) and rs11265461 (P = 1.94 × 10(-7)) are adjacent to signaling lymphocytic activation molecule family member 1 (SLAMF1); rs4699030 (P = 1.94 × 10(-6)) and rs230529 (P = 1.74 × 10(-7)) are located in the gene nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NFKB1); and rs13049286 (P = 3.05 × 10(-5)) and rs3827219 (P = 1.66 × 10(-5)) fall in receptor-interacting serine/threonine-protein kinase 4 (RIPK4). One isolated single nucleotide polymorphism (SNP), rs739617 (P = 3.87 × 10(-5)) was also identified to be associated with TRS. The -94delATTG allele (rs28362691) located in the promoter region of NFKB1 was identified by resequencing and was found to associate with TRS (P = 4.85 × 10(-6)). The promoter assay demonstrated that the -94delATTG allele had a significant lower promoter activity than the -94insATTG allele in the SH-SY5Y cells. This study suggests that rs28362691 in NFKB1 might be involved in the development of TRS.     

A genome-wide linkage and association scan reveals novel loci for hypertension and blood pressure traits

Hypertension is caused by the interaction of environmental and genetic factors. The condition which is very common, with about 18% of the adult Hong Kong Chinese population and over 50% of older individuals affected, is responsible for considerable morbidity and mortality. To identify genes influencing hypertension and blood pressure, we conducted a combined linkage and association study using over 500,000 single nucleotide polymorphisms (SNPs) genotyped in 328 individuals comprising 111 hypertensive probands and their siblings. Using a family-based association test, we found an association with SNPs on chromosome 5q31.1 (rs6596140; P<9 × 10(-8)) for hypertension. One candidate gene, PDC, was replicated, with rs3817586 on 1q31.1 attaining P = 2.5 × 10(-4) and 2.9 × 10(-5) in the within-family tests for DBP and MAP, respectively. We also identified regions of significant linkage for systolic and diastolic blood pressure on chromosomes 2q22 and 5p13, respectively. Further family-based association analysis of the linkage peak on chromosome 5 yielded a significant association (rs1605685, P<7 × 10(-5)) for DBP. This is the first combined linkage and association study of hypertension and its related quantitative traits with Chinese ancestry. The associations reported here account for the action of common variants whereas the discovery of linkage regions may point to novel targets for rare variant screening.