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1.  Combined linkage and family-based association analysis improves candidate gene detection in Genetic Analysis Workshop 18 simulation data 
BMC Proceedings  2014;8(Suppl 1):S29.
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.
doi:10.1186/1753-6561-8-S1-S29
PMCID: PMC4143774  PMID: 25519379
3.  Genetic Variants in ER Cofactor Genes and Endometrial Cancer Risk 
PLoS ONE  2012;7(8):e42445.
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 (Padjusted = 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.
doi:10.1371/journal.pone.0042445
PMCID: PMC3411617  PMID: 22876322
4.  Chromosome 2p14 Is Linked to Susceptibility to Leprosy 
PLoS ONE  2012;7(1):e29747.
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.
doi:10.1371/journal.pone.0029747
PMCID: PMC3253103  PMID: 22238647
5.  A Comprehensive Association Analysis of Homocysteine Metabolic Pathway Genes in Singaporean Chinese with Ischemic Stroke 
PLoS ONE  2011;6(9):e24757.
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 Ptrend = 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.
doi:10.1371/journal.pone.0024757
PMCID: PMC3174208  PMID: 21935458
6.  Genome-Wide Association Study for Atopy and Allergic Rhinitis in a Singapore Chinese Population 
PLoS ONE  2011;6(5):e19719.
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, Pcombined = 4.46×10−05) and BCAP SNP rs505010 on chromosome 10q24.1 (OR = 0.64, Pcombined = 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.
doi:10.1371/journal.pone.0019719
PMCID: PMC3098846  PMID: 21625490
7.  Genome-wide association study of follicular lymphoma identifies a risk locus at 6p21.32 
Nature genetics  2010;42(8):661-664.
To identify susceptibility loci for non-Hodgkin lymphoma (NHL) subtypes, we conducted a three-stage genome-wide association study. We identified two variants associated with follicular lymphoma (FL) in 1,465 FL cases/6,958 controls at 6p21.32 (rs10484561, rs7755224, r2=1.0; combined p-values=1.12×10-29, 2.00×10-19), providing further support that MHC genetic variation influences FL susceptibility. Confirmatory evidence of a previously reported association was also found between chronic lymphocytic leukemia/small lymphocytic lymphoma and rs735665 (combined p-value=4.24×10-9).
doi:10.1038/ng.626
PMCID: PMC2913472  PMID: 20639881
8.  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.
doi:10.1186/bcr2772
PMCID: PMC3046434  PMID: 21062454

Results 1-8 (8)