Conference Paper: Fine mapping on chromosome 10q24.2 implicates ADD3 in biliary atresia

TitleFine mapping on chromosome 10q24.2 implicates ADD3 in biliary atresia
Authors
Issue Date2012
PublisherAmerican Society of Human Genetics
Citation
The 62th Annual Meeting of American Society of Human Genetics (ASHG 2012), San Francisco, CA., 6-10 November 2012. How to Cite?
AbstractBiliary Atresia (BA [OMIM 210500]) is a major cause of neonatal cholestasis (arrest of the normal flow bile) and is characterized by progressive fibrosclerosing and inflammatory obliteration of the extrahepatic biliary system during the first few weeks of life. The only current treatment is surgical (portoenterostomy -Kasai operation). The condition presents mainly sporadically, with only a few familial cases reported. BA is a rare congenital disorder whose incidence varies widely among populations (from 1 in 5,000 in Asians to 1 in 18,000 in Caucasians), being most common in East Asia and Polynesia. Through a genome-wide association study (GWAS) on Chinese individuals we identified the association of a 129Kb BA-associated region on chromosome 10q24.2 encompassing two biologically plausible genes, ADD3 and XPNPEP1. The strongest association was for a Single Nucleotide Polymorphism (SNP; rs17095355; p=6.94x10-9), intergenic between ADD3 and XPNPEP1. To determine the genetic architecture within this region we increased the genotype density by genotyping 117 tag-SNPs in 339 Chinese BA patients and 389 Chinese controls and also used imputation. rs17095355 remained the most associated marker within the region (p=6.06 x10-9). To elucidate the risk-contribution model of regional variation, we performed stepwise regression and sequential conditional test of the genotyped SNPs with BA phenotype. The disease risk model included 6 SNPs (i.e. rs975442, rs17095355, rs10509906, rs11194975, rs2501577 and rs11194997), in which rs975442, rs10509906, rs11194975, rs11194997 were variants newly included in the fine mapping study but not in GWAS. In this model, rs10509906 was independently associated with BA (p=0.018 conditioned on rs17095355). This model explains 8.9% of the phenotypic variation (R2=0.031 in GWAS) and indicates that multiple variants may contribute to BA susceptibility. The risk alleles of rs17095355 and rs10509906 were ancestral, suggesting an ancestral-susceptibility model of BA pathogenesis. We found that the haplotype comprising the risk allele of rs17095355 was associated with reduced ADD3 gene expression in liver of BA patients. Thus, our data suggests that ADD3 expression level in BA liver may contribute to BA pathogenesis. ADD3 is a component of the actin-adducin-spectin complex which is known to be associated with pathologic cholestasis.
Persistent Identifierhttp://hdl.handle.net/10722/181801

 

DC FieldValueLanguage
dc.contributor.authorGarcia-Barcelo, MMen_US
dc.contributor.authorCheng, Gen_US
dc.contributor.authorTang, CSMen_US
dc.contributor.authorLiu, Xen_US
dc.contributor.authorZhang, Ren_US
dc.contributor.authorSo, MTen_US
dc.contributor.authorWong, EHMen_US
dc.contributor.authorChung, HYen_US
dc.contributor.authorChan, IHYen_US
dc.contributor.authorLiu, Jen_US
dc.contributor.authorZhong, Wen_US
dc.contributor.authorXia, Hen_US
dc.contributor.authorYu, Jen_US
dc.contributor.authorWong, KKYen_US
dc.contributor.authorCherny, SSen_US
dc.contributor.authorSham, PCen_US
dc.contributor.authorTam, PKHen_US
dc.date.accessioned2013-03-19T03:58:54Z-
dc.date.available2013-03-19T03:58:54Z-
dc.date.issued2012en_US
dc.identifier.citationThe 62th Annual Meeting of American Society of Human Genetics (ASHG 2012), San Francisco, CA., 6-10 November 2012.en_US
dc.identifier.urihttp://hdl.handle.net/10722/181801-
dc.description.abstractBiliary Atresia (BA [OMIM 210500]) is a major cause of neonatal cholestasis (arrest of the normal flow bile) and is characterized by progressive fibrosclerosing and inflammatory obliteration of the extrahepatic biliary system during the first few weeks of life. The only current treatment is surgical (portoenterostomy -Kasai operation). The condition presents mainly sporadically, with only a few familial cases reported. BA is a rare congenital disorder whose incidence varies widely among populations (from 1 in 5,000 in Asians to 1 in 18,000 in Caucasians), being most common in East Asia and Polynesia. Through a genome-wide association study (GWAS) on Chinese individuals we identified the association of a 129Kb BA-associated region on chromosome 10q24.2 encompassing two biologically plausible genes, ADD3 and XPNPEP1. The strongest association was for a Single Nucleotide Polymorphism (SNP; rs17095355; p=6.94x10-9), intergenic between ADD3 and XPNPEP1. To determine the genetic architecture within this region we increased the genotype density by genotyping 117 tag-SNPs in 339 Chinese BA patients and 389 Chinese controls and also used imputation. rs17095355 remained the most associated marker within the region (p=6.06 x10-9). To elucidate the risk-contribution model of regional variation, we performed stepwise regression and sequential conditional test of the genotyped SNPs with BA phenotype. The disease risk model included 6 SNPs (i.e. rs975442, rs17095355, rs10509906, rs11194975, rs2501577 and rs11194997), in which rs975442, rs10509906, rs11194975, rs11194997 were variants newly included in the fine mapping study but not in GWAS. In this model, rs10509906 was independently associated with BA (p=0.018 conditioned on rs17095355). This model explains 8.9% of the phenotypic variation (R2=0.031 in GWAS) and indicates that multiple variants may contribute to BA susceptibility. The risk alleles of rs17095355 and rs10509906 were ancestral, suggesting an ancestral-susceptibility model of BA pathogenesis. We found that the haplotype comprising the risk allele of rs17095355 was associated with reduced ADD3 gene expression in liver of BA patients. Thus, our data suggests that ADD3 expression level in BA liver may contribute to BA pathogenesis. ADD3 is a component of the actin-adducin-spectin complex which is known to be associated with pathologic cholestasis.-
dc.languageengen_US
dc.publisherAmerican Society of Human Genetics-
dc.relation.ispartofAnnual Meeting of American Society of Human Genetics, ASHG 2012en_US
dc.titleFine mapping on chromosome 10q24.2 implicates ADD3 in biliary atresiaen_US
dc.typeConference_Paperen_US
dc.identifier.emailGarcia-Barcelo, MM: mmgarcia@hku.hken_US
dc.identifier.emailCheng, G: chengguo@hku.hken_US
dc.identifier.emailLiu, X: liuxlai@hku.hken_US
dc.identifier.emailZhang, R: h1094156@hku.hken_US
dc.identifier.emailSo, MT: jaymtso@hku.hken_US
dc.identifier.emailWong, EHM: emilywongmm@yahoo.com.hken_US
dc.identifier.emailWong, KKY: kkywong@hku.hk-
dc.identifier.emailCherny, SS: cherny@hku.hk-
dc.identifier.emailSham, PC: pcsham@hku.hk-
dc.identifier.emailTam, PKH: paultam@hku.hk-
dc.identifier.authorityGarcia-Barcelo, MM=rp00445en_US
dc.identifier.authorityWong, KKY=rp01392en_US
dc.identifier.authorityCherny, SS=rp00232en_US
dc.identifier.authoritySham, PC=rp00459en_US
dc.identifier.authorityTam, PKH=rp00060en_US
dc.description.naturelink_to_OA_fulltext-
dc.identifier.hkuros213459en_US
dc.publisher.placeUnited States-

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