Genome-wide association study of Parkinson's disease in East Asians.

Genome-wide association studies (GWAS) on Parkinson's disease (PD) have mostly been done in Europeans and Japanese. No study has been done in Han Chinese, which make up nearly a fifth of the world population. We conducted the first Han Chinese GWAS analysing a total of 22,729 subjects (5,125 PD cases and 17,604 controls) from Singapore, Hong Kong, Malaysia, Korea, mainland China and Taiwan. We performed imputation, merging and logistic regression analyses of 2,402,394 SNPs passing quality control filters in 779 PD cases, 13,227 controls, adjusted for the first three principal components. 90 SNPs with association P < 10-4 were validated in 9 additional sample collections and the results were combined using fixed-effects inverse-variance meta-analysis. We observed strong associations reaching genome-wide significance at SNCA, LRRK2 and MCCC1, confirming their important roles in both European and Asian PD. We also identified significant (P < 0.05) associations at 5 loci (DLG2, SIPA1L2, STK39, VPS13C and RIT2), and observed the same direction of associations at 9 other loci including BST1 and PARK16. Allelic heterogeneity was observed at LRRK2 while European risk SNPs at 6 other loci including MAPT and GBA-SYT11 were non-polymorphic or very rare in our cohort. Overall, we replicate associations at SNCA, LRRK2, MCCC1 and 14 other European PD loci but did not identify Asian-specific loci with large effects (OR > 1.45) on PD risk. Our results also demonstrate some differences in the genetic contribution to PD between Europeans and Asians. Further pan-ethnic meta-analysis with European GWAS cohorts may unravel new PD loci.

Identification of Loci at 1q21 and 16q23 That Affect Susceptibility to Inflammatory Bowel Disease in Koreans.

Recent genome-wide association studies have identified more than 200 regions that affect susceptibility to inflammatory bowel disease (IBD). However, identified common variants account for only a fraction of IBD heritability and largely have been identified in populations of European ancestry. We performed a genome-wide association study of susceptibility loci in Korean individuals, comprising a total of 1505 IBD patients and 4041 controls. We identified 2 new susceptibility loci for IBD at genome-wide significance: rs3766920 near PYGO2-SHC1 at 1q21 and rs16953946 in CDYL2 at 16q23. In addition, we confirmed associations, in Koreans, with 28 established IBD loci (P < 2.16 × 10-4). Our findings support the complementary value of genetic studies in different populations.

Identification of Ten Additional Susceptibility Loci for Ulcerative Colitis Through Immunochip Analysis in Koreans.

BACKGROUND: Recent genetic association studies identified more than 160 susceptibility loci for inflammatory bowel disease in Caucasian populations, but studies in Asian populations are limited. We have previously reported 3 loci associated with Korean ulcerative colitis (UC). METHODS: Using the Immunochip custom single nucleotide polymorphisms (SNP) array designed for dense genotyping of 186 known disease loci from 12 immune-mediated diseases, we analyzed 705 patients with UC and 1178 controls for 536,821 SNPs (89,057 genotyped and 447,764 imputed) in the discovery stage followed by replication in additional 980 affected individuals and 2694 controls in a Korean population. RESULTS: We confirmed the associations of 10 known UC risk loci in Koreans: rs76418789 in IL23R (combined P = 1.25 × 10), rs4728142 in IRF5 (combined P = 3.17 × 10), rs1830610 near JAK2 (combined P = 2.28 × 10), rs1555791 near TNFRSF14 (combined P = 1.62 × 10), rs880790 between IL10-IL19 (combined P = 3.73 × 10), rs10185424 between IL1R2-IL1R1 (combined P = 1.54 × 10), rs6478108 in TNFSF15 (combined P = 9.28 × 10), rs861857 between UBE2L3-YDJC (combined P = 3.05 × 10), rs1801274 in FCGR2A (discovery P = 1.54 × 10), and rs17085007 between GPR12-USP12 (discovery P = 3.64 × 10). The percentage of phenotype variance explained by the 13 risk loci (including 3 previously reported loci) was 5.61% in Koreans (on the liability scale, population prevalence = 0.0308%). CONCLUSIONS: Our study increased the number of UC susceptibility loci in Koreans to 13 and highlighted the extensive sharing of genetic risk across populations of UC.

A genome-wide association study of n-3 and n-6 plasma fatty acids in a Singaporean Chinese population.

Polyunsaturated fatty acids (PUFAs) have a major impact on human health. Recent genome-wide association studies (GWAS) have identified several genetic loci that are associated with plasma levels of n-3 and n-6 PUFAs in primarily subjects of European ancestry. However, the relevance of these findings has not been evaluated extensively in other ethnic groups. The primary aim of this study was to evaluate for genetic loci associated with n-3 and n-6 PUFAs and to validate the role of recently identified index loci using data from a Singaporean Chinese population. Using a GWAS approach, we evaluated associations with plasma concentrations of three n-3 PUFAs [alphalinolenic acid (ALA), eicosapentaenoic acid and docosahexaenoic acid], four n-6 PUFAs [linoleic acid (LA), gammalinolenic acid, dihomogammalinolenic acid (DGLA) and arachidonic acid], and estimates of delta-5 desaturase and delta-6 desaturase activities among the participants (N = 1361) of the Singaporean Chinese Health Study. Our results reveal robust genome-wide associations (p value <5 × 10(-8)) with ALA, all four n-6 PUFAs, and delta-6 desaturase activity at the FADS1/FADS2 locus. We further replicated the associations between common index variants at the NTAN1/PDXDC1 locus and n-6 PUFAs LA and DGLA, and between the JMJD1C locus and n-6 PUFA LA (p value between 0.0490 and 9.88 × 10(-4)). These associations were independent of dietary intake of PUFAs. In aggregate, we show that genetic loci that influence plasma concentrations of n-3 and n-6 PUFAs are shared across different ethnic groups.

Identification of new susceptibility loci for IgA nephropathy in Han Chinese.

IgA nephropathy (IgAN) is one of the most common primary glomerulonephritis. Previously identified genome-wide association study (GWAS) loci explain only a fraction of disease risk. To identify novel susceptibility loci in Han Chinese, we conduct a four-stage GWAS comprising 8,313 cases and 19,680 controls. Here, we show novel associations at ST6GAL1 on 3q27.3 (rs7634389, odds ratio (OR)=1.13, P=7.27 × 10(-10)), ACCS on 11p11.2 (rs2074038, OR=1.14, P=3.93 × 10(-9)) and ODF1-KLF10 on 8q22.3 (rs2033562, OR=1.13, P=1.41 × 10(-9)), validate a recently reported association at ITGAX-ITGAM on 16p11.2 (rs7190997, OR=1.22, P=2.26 × 10(-19)), and identify three independent signals within the DEFA locus (rs2738058, P=1.15 × 10(-19); rs12716641, P=9.53 × 10(-9); rs9314614, P=4.25 × 10(-9), multivariate association). The risk variants on 3q27.3 and 11p11.2 show strong association with mRNA expression levels in blood cells while allele frequencies of the risk variants within ST6GAL1, ACCS and DEFA correlate with geographical variation in IgAN prevalence. Our findings expand our understanding on IgAN genetic susceptibility and provide novel biological insights into molecular mechanisms underlying IgAN.

Genome-wide meta-analysis identifies multiple novel associations and ethnic heterogeneity of psoriasis susceptibility.

Psoriasis is a common inflammatory skin disease with complex genetics and different degrees of prevalence across ethnic populations. Here we present the largest trans-ethnic genome-wide meta-analysis (GWMA) of psoriasis in 15,369 cases and 19,517 controls of Caucasian and Chinese ancestries. We identify four novel associations at LOC144817, COG6, RUNX1 and TP63, as well as three novel secondary associations within IFIH1 and IL12B. Fine-mapping analysis of MHC region demonstrates an important role for all three HLA class I genes and a complex and heterogeneous pattern of HLA associations between Caucasian and Chinese populations. Further, trans-ethnic comparison suggests population-specific effect or allelic heterogeneity for 11 loci. These population-specific effects contribute significantly to the ethnic diversity of psoriasis prevalence. This study not only provides novel biological insights into the involvement of immune and keratinocyte development mechanism, but also demonstrates a complex and heterogeneous genetic architecture of psoriasis susceptibility across ethnic populations.

Combined linkage and family-based association analysis improves candidate gene detection in Genetic Analysis Workshop 18 simulation data.

Because the genotype-phenotype correlation information is investigated differently by linkage and association analyses, various efforts have been made to model linkage and association jointly. However, joint modeling methods are usually computationally intensive; hence they cannot currently accommodate large pedigrees with dense markers. This article proposes a simple method to combine the linkage and association evidence with the aim of improving the detection power of disease susceptibility genes. Our detection power comparisons show that the combined linkage-association p values can improve remarkably the causal gene detection power in Genetic Analysis Workshop 18 simulation data.

Genetic variants in ER cofactor genes and endometrial cancer risk.

Given that the transcriptional regulatory activity of estrogen receptor (ER) is modulated by its biochemical cofactors, genetic variation within the ER cofactor genes may alter cellular response to estrogen exposure and consequently modify the risk for endometrial cancer. We genotyped 685 tagging SNPs within 60 ER cofactor genes in 564 endometrial cancer cases and 1,510 controls from Sweden, and tested their associations with the risk of endometrial cancer. We investigated the associations of individual SNPs by using a trend test as well as multiple SNPs within a gene or gene complex by using multi-variant association analysis. No significant association was observed for any individual SNPs or genes, but a marginal association of the cumulative genetic variation of the NCOA2 complex as a whole (NCOA2, CARM1, CREBBP, PRMT1 and EP300) with endometrial cancer risk was observed (P(adjusted) = 0.033). However, the association failed to be replicated in an independent European dataset of 1265 cases and 5190 controls (P = 0.71). The results indicate that common genetic variants within ER cofactor genes are unlikely to play a significant role in endometrial cancer risk in European population.

Chromosome 2p14 is linked to susceptibility to leprosy.

BACKGROUND: A genetic component to the etiology of leprosy is well recognized but the mechanism of inheritance and the genes involved are yet to be fully established. METHODOLOGY: A genome-wide single nucleotide polymorphism (SNP) based linkage analysis was carried out using 23 pedigrees, each with 3 to 7 family members affected by leprosy. Multipoint parametric and non-parametric linkage analyses were performed using MERLIN 1.1.1. PRINCIPAL FINDINGS: Genome-wide significant evidence for linkage was identified on chromosome 2p14 with a heterogeneity logarithm of odds (HLOD) score of 3.51 (rs1106577) under a recessive model of inheritance, while suggestive evidence was identified on chr.4q22 (HLOD 2.92, rs1349350, dominant model), chr. 8q24 (HLOD 2.74, rs1618523, recessive model) and chr.16q24 (HLOD 1.93, rs276990 dominant model). Our study also provided moderate evidence for a linkage locus on chromosome 6q24-26 by non-parametric linkage analysis (rs6570858, LOD 1.54, p = 0.004), overlapping a previously reported linkage region on chromosome 6q25-26. CONCLUSION: A genome-wide linkage analysis has identified a new linkage locus on chromosome 2p14 for leprosy in Pedigrees from China.

ARVCF genetic influences on neurocognitive and neuroanatomical intermediate phenotypes in Chinese patients with schizophrenia.

OBJECTIVE: There are notable similarities between velocardiofacial syndrome and schizophrenia in terms of neurocognitive deficits and brain structural abnormalities. These similarities have supported the role of the armadillo repeat gene deleted in velocardiofacial syndrome (ARVCF) as a susceptibility gene in schizophrenia. This study investigated the relationships between haplotypes of the ARVCF gene and specific intermediate phenotypes in schizophrenia. We hypothesized that ARVCF gene haplotypes influence caudate nucleus volume, fractional anisotropy, and neurocognitive functioning in schizophrenia. METHOD: Between May 2006 and November 2009, 200 Chinese participants (125 patients with DSM-IV diagnosis of schizophrenia and 75 controls) were genotyped using blood samples, and a subset of 166 participants (99 patients with DSM-IV diagnosis of schizophrenia and 67 controls) underwent structural magnetic resonance imaging, diffusion tensor imaging, and completed neuropsychological testing. RESULTS: The haplotype T-G-A-T-T-G-G-C-T-G-T (ARVCF-Hap1) was significantly associated with fractional anisotropy of the caudate nucleus and executive functioning in patients. Specifically, patients with more copies of ARVCF-Hap1 have lower white matter integrity in caudate nucleus (P = .0008) and greater perseverative errors (P = .00003) on the Wisconsin Card Sorting Test. A trend of lower caudate volume (P = .015) in patients with more copies of ARVCF-Hap1 was also observed. CONCLUSIONS: These findings are consistent with known ARVCF gene effects on neurodevelopment in terms of cellular arrangement, migration, and intracellular signaling involving the striatum and may involve interactions with other brain networks such as prefrontal cortex, and they underscore the importance of imaging-genetic studies to elucidate the genetic influences underlying intermediate phenotypes in complex neurobehavioral disorders.

A genome-wide association study in Han Chinese identifies new susceptibility loci for ankylosing spondylitis.

To identify susceptibility loci for ankylosing spondylitis, we performed a two-stage genome-wide association study in Han Chinese. In the discovery stage, we analyzed 1,356,350 autosomal SNPs in 1,837 individuals with ankylosing spondylitis and 4,231 controls; in the validation stage, we analyzed 30 suggestive SNPs in an additional 2,100 affected individuals and 3,496 controls. We identified two new susceptibility loci between EDIL3 and HAPLN1 at 5q14.3 (rs4552569; P = 8.77 × 10(-10)) and within ANO6 at 12q12 (rs17095830; P = 1.63 × 10(-8)). We also confirmed previously reported associations in Europeans within the major histocompatibility complex (MHC) region (top SNP, rs13202464; P < 5 × 10(-324)) and at 2p15 (rs10865331; P = 1.98 × 10(-8)). We show that rs13202464 within the MHC region mainly represents the risk effect of HLA-B*27 variants (including HLA-B*2704, HLA-B*2705 and HLA-B*2715) in Chinese. The two newly discovered loci implicate genes related to bone formation and cartilage development, suggesting their potential involvement in the etiology of ankylosing spondylitis.

A genome-wide association study in Han Chinese identifies multiple susceptibility loci for IgA nephropathy.

We performed a two-stage genome-wide association study of IgA nephropathy (IgAN) in Han Chinese, with 1,434 affected individuals (cases) and 4,270 controls in the discovery phase and follow-up of the top 61 SNPs in an additional 2,703 cases and 3,464 controls. We identified associations at 17p13 (rs3803800, P = 9.40 × 10(-11), OR = 1.21; rs4227, P = 4.31 × 10(-10), OR = 1.23) and 8p23 (rs2738048, P = 3.18 × 10(-14), OR = 0.79) that implicated the genes encoding tumor necrosis factor (TNFSF13) and α-defensin (DEFA) as susceptibility genes. In addition, we found multiple associations in the major histocompatibility complex (MHC) region (rs660895, P = 4.13 × 10(-20), OR = 1.34; rs1794275, P = 3.43 × 10(-13), OR = 1.30; rs2523946, P = 1.74 × 10(-11), OR = 1.21) and confirmed a previously reported association at 22q12 (rs12537, P = 1.17 × 10(-11), OR = 0.78). We also found that rs660895 was associated with clinical subtypes of IgAN (P = 0.003), proteinuria (P = 0.025) and IgA levels (P = 0.047). Our findings show that IgAN is associated with variants near genes involved in innate immunity and inflammation.

A comprehensive association analysis of homocysteine metabolic pathway genes in Singaporean Chinese with ischemic stroke.

BACKGROUND: The effect of genetic factors, apart from 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphisms, on elevated plasma homocysteine levels and increasing ischemic stroke risk have not been fully elucidated. We conducted a comprehensive analysis of 25 genes involved in homocysteine metabolism to investigate association of common variants within these genes with ischemic stroke risk. METHODOLOGY/PRINCIPAL FINDINGS: The study was done in two stages. In the initial study, SNP and haplotype-based association analyses were performed using 147 tagging Single Nucleotide Polymorphisms (SNPs) in 360 stroke patients and 354 non-stroke controls of Singaporean Chinese ethnicity. Joint association analysis of significant SNPs was then performed to assess the cumulative effect of these variants on ischemic stroke risk. In the replication study, 8 SNPs were selected for validation in an independent set of 420 matched case-control pairs of Singaporean Chinese ethnicity. SNP analysis from the initial study suggested 3 risk variants in the MTRR, SHMT1 and TCN2 genes which were moderately associated with ischemic stroke risk, independent of known stroke risk factors. Although the replication study failed to support single-SNP associations observed in the initial study, joint association analysis of the 3 variants in combined initial and replication samples revealed a trend of elevated risk with an increased number of risk alleles (Joint P(trend) = 1.2×10(-6)). CONCLUSIONS: Our study did not find direct evidence of associations between any single polymorphisms of homocysteine metabolic pathway genes and ischemic stroke, but suggests that the cumulative effect of several small to moderate risk variants from genes involved in homocysteine metabolism may jointly confer a significant impact on ischemic stroke risk.

Genome-wide association study for atopy and allergic rhinitis in a Singapore Chinese population.

Allergic rhinitis (AR) is an atopic disease which affects about 600 million people worldwide and results from a complex interplay between genetic and environmental factors. However genetic association studies on known candidate genes yielded variable results. The aim of this study is to identify the genetic variants that influence predisposition towards allergic rhinitis in an ethnic Chinese population in Singapore using a genome-wide association study (GWAS) approach. A total of 4461 ethnic Chinese volunteers were recruited in Singapore and classified according to their allergic disease status. The GWAS included a discovery stage comparing 515 atopic cases (including 456 AR cases) and 486 non-allergic non-rhinitis (NANR) controls. The top SNPs were then validated in a replication cohort consisting of a separate 2323 atopic cases (including 676 AR cases) and 511 NANR controls. Two SNPs showed consistent association in both discovery and replication phases; MRPL4 SNP rs8111930 on 19q13.2 (OR = 0.69, P(combined) = 4.46×10(-05)) and BCAP SNP rs505010 on chromosome 10q24.1 (OR = 0.64, P(combined) = 1.10×10(-04)). In addition, we also replicated multiple associations within known candidates regions such as HLA-DQ and NPSR1 locus in the discovery phase. Our study suggests that MRPL4 and BCAP, key components of the HIF-1α and PI3K/Akt signaling pathways respectively, are two novel candidate genes for atopy and allergic rhinitis. Further study on these molecules and their signaling pathways would help in understanding of the pathogenesis of allergic rhinitis and identification of targets for new therapeutic intervention.

A combined analysis of genome-wide association studies in breast cancer.

In an attempt to identify common disease susceptibility alleles for breast cancer, we performed a combined analysis of three genome-wide association studies (GWAS), involving 2,702 women of European ancestry with invasive breast cancer and 5,726 controls. Tests for association were performed for 285,984 SNPs. Evidence for association with SNPs in genes in specific pathways was assessed using a permutation-based approach. We confirmed associations with loci reported by previous GWAS on 1p11.2, 2q35, 3p, 5p12, 8q24, 10q23.13, 14q24.1 and 16q. Six SNPs with the strongest signals of association with breast cancer, and which have not been reported previously, were typed in two further studies; however, none of the associations could be confirmed. Suggestive evidence for an excess of associations was found for genes involved in the regulation of actin cytoskeleton, glycan degradation, alpha-linolenic acid metabolism, circadian rhythm, hematopoietic cell lineage and drug metabolism. Androgen and oestrogen metabolism, a pathway previously found to be associated with the development of postmenopausal breast cancer, was marginally significant (P = 0.051 [unadjusted]). These results suggest that further analysis of SNPs in these pathways may identify associations that would be difficult to detect through agnostic single SNP analyses. More effort focused in these aspects of oncology can potentially open up promising avenues for the understanding of breast cancer and its prevention.

A genome-wide association scan on estrogen receptor-negative breast cancer.

INTRODUCTION: Breast cancer is a heterogeneous disease and may be characterized on the basis of whether estrogen receptors (ER) are expressed in the tumour cells. ER status of breast cancer is important clinically, and is used both as a prognostic indicator and treatment predictor. In this study, we focused on identifying genetic markers associated with ER-negative breast cancer risk. METHODS: We conducted a genome-wide association analysis of 285,984 single nucleotide polymorphisms (SNPs) genotyped in 617 ER-negative breast cancer cases and 4,583 controls. We also conducted a genome-wide pathway analysis on the discovery dataset using permutation-based tests on pre-defined pathways. The extent of shared polygenic variation between ER-negative and ER-positive breast cancers was assessed by relating risk scores, derived using ER-positive breast cancer samples, to disease state in independent, ER-negative breast cancer cases. RESULTS: Association with ER-negative breast cancer was not validated for any of the five most strongly associated SNPs followed up in independent studies (1,011 ER-negative breast cancer cases, 7,604 controls). However, an excess of small P-values for SNPs with known regulatory functions in cancer-related pathways was found (global P = 0.052). We found no evidence to suggest that ER-negative breast cancer shares a polygenic basis to disease with ER-positive breast cancer. CONCLUSIONS: ER-negative breast cancer is a distinct breast cancer subtype that merits independent analyses. Given the clinical importance of this phenotype and the likelihood that genetic effect sizes are small, greater sample sizes and further studies are required to understand the etiology of ER-negative breast cancers.

Genome-wide association study of follicular lymphoma identifies a risk locus at 6p21.32.

To identify susceptibility loci for non-Hodgkin lymphoma subtypes, we conducted a three-stage genome-wide association study. We identified two variants associated with follicular lymphoma at 6p21.32 (rs10484561, combined P = 1.12 x 10(-29) and rs7755224, combined P = 2.00 x 10(-19); r(2) = 1.0), supporting the idea that major histocompatibility complex genetic variation influences follicular lymphoma susceptibility. We also found confirmatory evidence of a previously reported association between chronic lymphocytic leukemia/small lymphocytic lymphoma and rs735665 (combined P = 4.24 x 10(-9)).

A genome-wide association study of nasopharyngeal carcinoma identifies three new susceptibility loci.

To identify genetic susceptibility loci for nasopharyngeal carcinoma (NPC), a genome-wide association study was performed using 464,328 autosomal SNPs in 1,583 NPC affected individuals (cases) and 1,894 controls of southern Chinese descent. The top 49 SNPs from the genome-wide association study were genotyped in 3,507 cases and 3,063 controls of southern Chinese descent from Guangdong and Guangxi. The seven supportive SNPs were further confirmed by transmission disequilibrium test analysis in 279 trios from Guangdong. We identified three new susceptibility loci, TNFRSF19 on 13q12 (rs9510787, Pcombined=1.53x10(-9), odds ratio (OR)=1.20), MDS1-EVI1 on 3q26 (rs6774494, Pcombined=1.34x10(-8), OR=0.84) and the CDKN2A-CDKN2B gene cluster on 9p21 (rs1412829, Pcombined=4.84x10(-7), OR=0.78). Furthermore, we confirmed the role of HLA by revealing independent associations at rs2860580 (Pcombined=4.88x10(-67), OR=0.58), rs2894207 (Pcombined=3.42x10(-33), OR=0.61) and rs28421666 (Pcombined=2.49x10(-18), OR=0.67). Our findings provide new insights into the pathogenesis of NPC by highlighting the involvement of pathways related to TNFRSF19 and MDS1-EVI1 in addition to HLA molecules.

Genomewide association study of leprosy.

BACKGROUND: The narrow host range of Mycobacterium leprae and the fact that it is refractory to growth in culture has limited research on and the biologic understanding of leprosy. Host genetic factors are thought to influence susceptibility to infection as well as disease progression. METHODS: We performed a two-stage genomewide association study by genotyping 706 patients and 1225 controls using the Human610-Quad BeadChip (Illumina). We then tested three independent replication sets for an association between the presence of leprosy and 93 single-nucleotide polymorphisms (SNPs) that were most strongly associated with the disease in the genomewide association study. Together, these replication sets comprised 3254 patients and 5955 controls. We also carried out tests of heterogeneity of the associations (or lack thereof) between these 93 SNPs and disease, stratified according to clinical subtype (multibacillary vs. paucibacillary). RESULTS: We observed a significant association (P<1.00x10(-10)) between SNPs in the genes CCDC122, C13orf31, NOD2, TNFSF15, HLA-DR, and RIPK2 and a trend toward an association (P=5.10x10(-5)) with a SNP in LRRK2. The associations between the SNPs in C13orf31, LRRK2, NOD2, and RIPK2 and multibacillary leprosy were stronger than the associations between these SNPs and paucibacillary leprosy. CONCLUSIONS: Variants of genes in the NOD2-mediated signaling pathway (which regulates the innate immune response) are associated with susceptibility to infection with M. leprae.