Gene‐Based Meta‐Analysis of Genome‐Wide Association Study Data Identifies Independent Single‐Nucleotide Polymorphisms in <i>ANXA6</i> as Being Associated With Systemic Lupus Erythematosus in Asian Populations

Zhang, Jing; Zhang, Yan; Yang, Jing; Guo, Mengbiao; Sun, Liangdan; Pan, Hai‐Feng; Hirankarn, Nattiya; Ying, Dingge; Zeng, Shuai; Lee, Tsz Leung; Lau, Chak Sing; Chan, Tak Mao; Leung, Alexander Moon Ho; Mok, Chi Chiu; Wong, Sik Nin; Lee, Ka Wing; Ho, Marco Hok Kung; Chung, Brian Hon‐Yin; Chong, Chun Yin; Wong, Raymond Woon Sing; Mok, Mo Yin; Wong, Wilfred Hing Sang; Tong, Kwok Lung; Tse, Niko Kei Chiu; Li, Xiang-Pei; Avihingsanon, Yingyos; Rianthavorn, Pornpimol; Deekajorndej, Thavatchai; Suphapeetiporn, Kanya; Shotelersuk, Vorasuk; Ying, Shirley King Yee; Fung, Samuel; Lai, Wai Ming; García-Barceló, María-Mercé; Cherny, Stacey S.; Sham, Pak C.; Cui, Yong; Yang, Sen; Ye, Dong‐Qing; Zhang, Xuejun; Lau, Yu Lung; Yang, Wanling

doi:10.1002/art.39275

Cited by 14 publications

(11 citation statements)

References 52 publications

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“…When assumed this way, genome-wide corrections such as Bonferroni lose power to identify the myriad of variants responsible for the phenotypic heterogeneity of a complex disorder. Similarly, more than one gene may exist at a locus for a complex disorder as exemplified by the identification of ANXA6 as a SLE gene located immediately downstream of TNIP1 (Zhang et al 2015). Hence, LD-based clustering algorithms such as OASIS that focus association signals to loci are of critical importance and can be followed up by biological studies for verification of particular genes.…”

Section: Discussionmentioning

confidence: 99%

“…Gene-based replication was performed using Gene-based Association Test using Extended Simes procedure (GATES) (Li et al 2011) as implemented in the KGG software (Li et al 2010). SNPs were mapped onto genes according to positional information from the NCBI GRCh37 database, and SNPs within 10 kb upstream and 10 kb downstream of each gene were included as well (Zhang et al 2015). OASIS candidate genes were used as the seed list for GATES verification.…”

Section: Methodsmentioning

confidence: 99%

“…Here, this principle is expanded upon by the development of a novel clustering algorithm to identify genes and loci of interest in SLE. As previously shown, gene- or region-based association analysis is an approach that may improve the power of GWAS and allow detection of genes of modest influence (Zhang et al 2015). It is known that true genetic associations are accompanied by signals from surrounding markers; i.e., single-nucleotide polymorphisms (SNPs) in LD with the susceptibility mutation also have statistically significant P values (Martin et al 2000).…”

Section: Introductionmentioning

confidence: 99%

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Novel linkage disequilibrium clustering algorithm identifies new lupus genes on meta-analysis of GWAS datasets

Saeed

2017

Immunogenetics

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Systemic lupus erythematosus (SLE) is a complex disorder. Genetic association studies of complex disorders suffer from the following three major issues: phenotypic heterogeneity, false positive (type I error), and false negative (type II error) results. Hence, genes with low to moderate effects are missed in standard analyses, especially after statistical corrections. OASIS is a novel linkage disequilibrium clustering algorithm that can potentially address false positives and negatives in genome-wide association studies (GWAS) of complex disorders such as SLE. OASIS was applied to two SLE dbGAP GWAS datasets (6077 subjects; ∼0.75 million single-nucleotide polymorphisms). OASIS identified three known SLE genes viz. IFIH1, TNIP1, and CD44, not previously reported using these GWAS datasets. In addition, 22 novel loci for SLE were identified and the 5 SLE genes previously reported using these datasets were verified. OASIS methodology was validated using single-variant replication and gene-based analysis with GATES. This led to the verification of 60% of OASIS loci. New SLE genes that OASIS identified and were further verified include TNFAIP6, DNAJB3, TTF1, GRIN2B, MON2, LATS2, SNX6, RBFOX1, NCOA3, and CHAF1B. This study presents the OASIS algorithm, software, and the meta-analyses of two publicly available SLE GWAS datasets along with the novel SLE genes. Hence, OASIS is a novel linkage disequilibrium clustering method that can be universally applied to existing GWAS datasets for the identification of new genes.Electronic supplementary materialThe online version of this article (doi:10.1007/s00251-017-0976-8) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Novel linkage disequilibrium clustering algorithm identifies new lupus genes on meta-analysis of GWAS datasets

Saeed

2017

Immunogenetics

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“…In particular, numerous genome‐wide association studies (GWAS) have been performed in SLE patients across different ethnicities and have led to the discovery of over 60 confirmed genetic risk loci. GWAS in Asia has contributed greatly to the advancement of lupus genetics and several susceptibility genes were in fact first reported in Asian patients prior to subsequent reports in other ethnic groups . Most recently, high density genotyping conducted on almost 4500 patients from Korean, Chinese, Malaysian and Japanese cohorts identified ten additional novel risk loci and increased the explained total heritability of SLE to 24% in Asians; and a combined Asian and European GWAS meta‐analysis also found numerous previously unreported SLE loci and suggested a possible genetic basis for the higher prevalence of SLE in Asians .…”

Section: Introductionmentioning

confidence: 99%

“…GWAS in Asia has contributed greatly to the advancement of lupus genetics and several susceptibility genes were in fact first reported in Asian patients prior to subsequent reports in other ethnic groups. 6 Most recently, high density genotyping conducted on almost 4500 patients from Korean, Chinese, Malaysian and Japanese cohorts identified ten additional novel risk loci and increased the explained total heritability of SLE to 24% in Asians; 7 and a combined Asian and European GWAS meta-analysis also found numerous previously unreported SLE loci and suggested a possible genetic basis for the higher prevalence of SLE in Asians. 8 Larger international research collaborations, with the increasing involvement from Asian countries, will likely become the new norm for lupus research in the future.…”

Section: Introductionmentioning

confidence: 99%

Lupus in the far east: a modern epidemic

Lau

2017

Int J of Rheum Dis

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Systemic lupus erythematosus (SLE) is a diverse and heterogeneous disease with much variation between different ethnicities. Although more severe and prevalent in non-Caucasian populations, the bulk of evidence regarding 'Asian lupus' had traditionally been extrapolated from studies on patient minorities in the West. Lupus research in Asia has since grown exponentially and now takes a leading role in improving the care for SLE patients worldwide. With recent advances, particularly from studies in population-specific phenotyping, genome-wide association studies, lupus nephritis and innovative treatment modalities, we now have an expanding understanding of both the basic science and clinical management of SLE. Upcoming breakthroughs from growing multi-ethnic cohorts and international collaborations will likely bring further important ramifications for SLE management in the near future.

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Genetic studies on systemic lupus erythematosus in East Asia point to population differences in disease susceptibility

Wang

Lau

Yang

2019

American J of Med Genetics Pt C

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Systemic lupus erythematosus (SLE) is a prototype autoimmune disease with extreme clinical heterogeneity and significant differences between populations. East Asian populations are known to have higher prevalence and more severe clinical manifestations for SLE than Europeans. The difference could be the result of genetic and environmental factors, and the interactions between them. Thus, identifying genetic associations from diverse populations provides an opportunity to better understand the genetic architecture of this heterogeneous disease. It is also necessary to elucidate population differences and to apply the findings in future stratified treatment of the disease, with ethnicity likely a major factor to consider. Indeed, it has shown that there are significant differences between East Asians and European populations in several genetic loci for SLE. Genetic studies on SLE are very active in East Asian countries and there have been close collaborations among scientists in this region. Here, we document some work done in this region on SLE genetic research and discuss the aspect of population differences.

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Gene‐Based Meta‐Analysis of Genome‐Wide Association Study Data Identifies Independent Single‐Nucleotide Polymorphisms in ANXA6 as Being Associated With Systemic Lupus Erythematosus in Asian Populations

Cited by 14 publications

References 52 publications

Novel linkage disequilibrium clustering algorithm identifies new lupus genes on meta-analysis of GWAS datasets

Novel linkage disequilibrium clustering algorithm identifies new lupus genes on meta-analysis of GWAS datasets

Lupus in the far east: a modern epidemic

Genetic studies on systemic lupus erythematosus in East Asia point to population differences in disease susceptibility

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