online ML Comm ORIGINAL ARTICLE Korean J Biol Psychiatry 2012;19:140-145 ISSN 1225-8709 / eissn 2005-7571 ST8SIA2 성균관대학교의과대학삼성서울병원정신건강의학교실, 1 삼성생명과학연구소임상의학연구센터, 2 서울대학교자연과학대학통계학과, 3 용인정신병원, 4 서울대학교의과대학서울대학교병원정신건강의학교실 5 유재현 1 류승형 1 조은영 2 허익수 3 박태성 3 이유상 4 권준수 5 홍경수 1,2 Association Analyses of ST8SIA2 Genetic Polymorphisms with Schizophrenia in the Korean Population Jae Hyun Yoo, MD, 1 Seunghyong Ryu, MD, 1 Eun Young Cho, MS, 2 Ik-Soo Huh, BS, 3 Taesung Park, PhD, 3 Yu-Sang Lee, MD, 4 Jun Soo Kwon, MD, 5 Kyung Sue Hong, MD 1,2 1 Department of Psychiatry, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea 2 Samsung Biomedical Research Institute, Center for Clinical Medicine, Seoul, Korea 3 Department of Statistics, College of Natural Science, Seoul National University, Seoul, Korea 4 Yong-In Mental Hospital, Yongin, Korea 5 Department of Psychiatry, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Korea ObjectivesZZST8SIA2 (ST8 alpha-n-acetyl-neuraminide alpha-2, 8-sialyltransferase 2 gene) is located at 15q26, a susceptibility locus for schizophrenia. Some previous research had indicated that single-nucleotide polymorphisms (SNPs) in the promoter region of ST8SIA2 were associated with schizophrenia in Japanese and Chinese populations. We investigated the association between SNPs in the promoter region of ST8SIA2 and schizophrenia in the Korean population. MethodsZZThe study subjects were 190 Korean patients with schizophrenia and 190 healthy controls. We performed allelic, genotypic, and haplotypic association analyses for rs3759916, rs3759915 and rs3759914 of ST8SIA2. All genotypes were determined by direct sequencing. ResultsZZIn the genotype-based analysis, rs3759914 showed a nominally significant association with schizophrenia under recessive genotypic model (p = 0.047). However, this association did not remain statistically significant after correction for multiple testing. Both allelic and haplotype analyses did not show any significant association. ConclusionsZZThese findings suggest that ST8SIA2 does not play a major role in the susceptibility to schizophrenia in the Korean population. Further studies with a larger number of subjects are required to definitively rule out minor effects of this gene on schizophrenia vulnerability. Key WordsZZST8SIA2 ㆍ Schizophrenia ㆍ Genetic polymorphism ㆍ Association. Received: June 19, 2012 / Revised: July 11, 2012 / Accepted: July 17, 2012 Address for correspondence: Kyung Sue Hong, MD Department of Psychiatry, Sungkyunkwan University School of Medicine, Samsung Medical Center, 50 Irwon-dong, Gangnam-gu, Seoul 135-710, Korea Tel: +82-2-3410-3584, Fax: +82-2-3410-0050, E-mail: hongks@skku.edu 조현병 (schizophrenia) 은유전인자가발병에중요한역할을하는것으로알려져있으며, 가족연구, 쌍생아연구, 입양아연구등에의하면 83~87% 정도의높은유전율 (heritability) 1-3) 을보이는질환이다. 현재까지조현병과관련이있다고알려진유전자로는 Dysbindin, Neuregulin 1, Catechol-O-methyl transferase 등이있으며, 2p, 5q, 3p, 11q, 2q, 1q, 22q, 8p, 6p, 20p, 14q 등의염색체좌 (chromosomal region) 또한광범위유전체연구 (genome-wide study) 에서의미있는결과를보여관련성이추정되고있다. 4) 15q26 염색체좌또한몇몇광범위유전체연관연구 (genome-wide linkage study) 에서조현병과양극성정동장애에서공통적으로연관성을보이는것으로나타나관심을끌고있다. 5)6) 140 Copyright 2012 Korean Society of Biological Psychiatry
No Association between ST8SIA2 and Schizophrenia Yoo JH, et al 특히, ST8 alpha-n-acetyl-neuraminide alpha-2, 8-sialyltransferase 2 유전자 ( 이하 ST8SIA2) 는 15q26 염색체좌에위치한후보유전자로서, 신경발생 (neurogenesis) 과정에중요한역할을한다고알려져있다. ST8SIA2로부터형성되는단백질은신경세포부착분자 1(neural cell adhesion molecule 1, 이하 NCA- M1) 과폴리시알산 (polysialic acid, 이하 PSA) 의결합을조절하는역할을하며, 7) PSA와결합한 NCAM1 은주로성인의해마 (hippocampus) 나후각망울 (olfactory bulb) 에위치하여신경세포의이주 (neural cell migration), 8)9) 신경돌기의증식 (neurite outgrowth), 10)11) 신경세포의유도 (neural path finding), 12) 시냅스의형성 (synaptogenesis), 13) 공간학습및기억 (spatial learning and memory) 14) 등을촉진한다. 그런데조현병환자의해마에서는이물질에대한면역반응세포의수가감소하고, 15) 후각망울의부피가감소하는등의연구결과가관찰되었다. 16) 또한, ST8SIA2 유전자결핍쥐에서나타나는치아이랑 (dentate gyrus) 및해마의 PSA 결핍소견 17) 은이유전자가조현병에서확인된신경조직의구성및해마기능과관련된장애와밀접한관련이있음을예측하게한다. 일본과중국에서는이러한 ST8SIA2 의역할및염색체좌 (15q- 26) 에주목하여, 조현병과의연관성을탐색하는연구가이루어졌다. Arai 등 18) 은일본인에서연합연구 (association study) 를시행하여, ST8SIA2 유전자전사조절부위 (promoter) 에위치한단일염기다형성 (single nucleotide polymorphism, 이하 SNP) rs3759916 과 rs3759914 가조현병과유의한연합을보임을보고하였다. 중국인을대상으로한 Tao 등 19) 의연합연구에서는 rs- 3759915 가조현병과연합을보이는것으로나타났다. 이러한배경에서 ST8SIA2는조현병의중요한후보유전자가될수있는데, 한국인을대상으로한연합연구는아직까지시행된바없다. 따라서본연구는기존연구에서조현병과의연합을나타낸 ST8SIA2 전사조절부위의 SNPs이한국인조현병환자에서도병과연관성을가지는지알아보고자하였다. 대상환자선정 연구대상은삼성서울병원, 용인정신병원에서 1년이상입원및외래통원치료를받은 18세이상 75세이하의환자중정신과의사에의해 Diagnostic and Statistical Manual of Mental Disorders-4 th Edition 진단기준 20) 의조현병으로진단된환자로하였다. 연구에참여한환자는총 190명이었으며, 정상군으로는지역사회로부터정신과적병력및가족력이없는건강한성인 190명을모집하였다. 초발정신증 (first episode psychosis) 및치료기간이 1년이하인환자는진단의안정성이확립 되어있지않아본연구에서는제외하였으며, 정상군중 4촌이내에정신과적가족력이있는경우도제외하였다. 본연구는삼성서울병원과용인정신병원윤리위원회 (Institutional Review Board) 에서승인을받았고, 모든참여자에게연구에대한설명을제공하고동의서를받았다. SNP 선정및유전형분석 ST8SIA2의전사조절부위에위치한세개의 SNP(SNP1 ; -1126 T > C ; rs3759916, SNP2 ; -907 G > C ; rs3759915, SNP3 ; -851 T > C ; rs3759914) 을표지자로선정하였다. 이들표지자들은아시아인구집단에서높은연관불균형 (linkage disequilibrium) 을보이며, 특히 Arai 등 18) 및 Tao 등 19) 의선행연합연구들에서조현병과의연합이지속적으로시사되고있다 (Fig. 1). 말초혈액으로부터 Wizard TM Genomic purification kit(promega, Medison, USA) 를이용하여 genomic DNA를추출하였으며, ABI PRISM BigDye Terminator v3.1 Cycle Sequencing kit(applied Biosystems, USA) 를이용하여표지자의유전자형을분석하였다. 유전자형분석은모든대상자들에서성공적으로분석되었다. 통계분석조현병환자군과정상군에서연령, 성별등의인구학적변수를카이제곱검정 (chi-square test) 및티검정 (t-test) 을사용하여비교하였다. 또한각각의표지자가 Hardy-Weinberg 평형을따르는지를정상군을대상으로 Haploview 를사용하여확인하였다. 세 SNPs에대해서각각대립유전자연합 (allelic association) 및유전자형연합 (genotypic association) 을분석하였고, 유전자형분석에는부가적 (additive), 우성 (dominant), 열성 (recessive) 및공동우성 (co-dominant) 의유전양식 (mode of transmission) 을가정하였다. 부가적유전양식의경우, 대립유전자의수가많아짐에따라조현병의발병이증가하는지확인하기위하여코크란아미티지추세검정 (Cochran-Armitage trend test) 를사용하였으며, 나머지유전양식에대해서는카이제곱검정을사용하여통계적검증을시행하였다. 추가적으로, Haploview 의 default confidence interval algorithm을통해구성된일배체블록 (rs3759916-rs3759915-rs3759914) 에대한일배체연합 (haplotypic association) 분석을시행하였다. 모든통계분석에는 SAS version 9.1(SAS institute) 및 Haploview v4.2(http://www.broadinstitute.org/haploview/haploview) 을사용하였다. 다중검사오류 (multiple testing error) 를보정하기위해서유의수준은 p value < 0.017(0.05/3) 로하였다. journal.biolpsychiatry.or.kr 141
Korean J Biol Psychiatry 2012;19:140-145 연구대상의인구학적특성을조사하였을때, 조현병환자군의평균연령은 28.40 ± 4.23세, 정상군은 32.97 ± 8.90세로나타나, 통계적으로의미있는차이를보이고있었다 (p < 0.001). 정상군 ( 남자 101 명, 여자 89명 ) 은조현병환자군 ( 남자 95명, 여자 95명 ) 보다남자의비율이높았지만, 성별에따른유의한차이는관찰되지않았다 (p = 0.538). 조현병환자군의평균발병연령은 23.34 ± 5.80세였으며, 아형으로는망상형이 111 명으로가장많았고, 미분화형 18명, 파과형 9명, 잔류형 3명순으로나 타났다. 세 SNPs의유전적분포는모두 Hardy-Weinberg 평형을위배하지않았다 (Table 1). 각각의 SNP과조현병발병사이의유전자형및대립유전자연합분석에서세 SNP 모두유의한연합을나타내지않았다 (Table 2). 열성유전방식의가정하에서 rs3759914 의 CC 유전자형은정상군에비해환자군에서높은빈도로나타나고있었으며, 조현병발병과의연합이 p < 0.05 수준에서유의하게나타났다 (p = 0.047)(Table 3). 그러나다중검사오류보정시에는유의성이유지되지않았다. rs3759916-rs3759915-rs3759914 의세 SNPs으로구성된일 Exon : ATG TAG 1 2 3 4 5 6 Arai et al. 18) Tao et al. 18) This study rs3759916 rs3759915 rs3759914.014.007.0036.039 rs3743365 rs3743364 rs3848153 rs3931230 rs2242113 rs8035191 Glu141Lys IVS4+63A>G rs2168351 rs2305561 IVS5+6C>T rs3784727 rs3784724 Fig. 1. ST8SIA2 organization and single-nucleotide polymorphism (SNP) locations (from the University of California at Santa Cruz Genome Browser, Feb. 2009). Exons were numbered and location of the initiation codon (ATG) and stop codon (TAA or TAG) were denoted. Minus signs ( ) indicate SNPs studied, but did not show statistically significant associa-tion in previous studies and this study, respectively. The SNP showing p value < 0.05 represented as numeric values. Table 1. Characteristics of SNP markers on ST8SIA2 142 SNP Location SNP type HWE test (p value) Allele MAF rs3759916 90737173 neargene-5* 0.192 T > C 0.329 rs3759915 90737392 neargene-5* 0.342 G > C 0.455 rs3759914 90737448 neargene-5* 0.141 T > C 0.316 * : Estimated promoter region of ST8SIA2. SNP : single-nucleotide polymorphism, HWE : Hardy-Weinberg equilibrium, MAF : minor allele frequency Table 2. Genotypic and allelic association analyses SNP Genotype count (%) p value Allele count (%) p value rs3759916 TT TC CC 0.116 T C 0.196 Schizophrenia 77 (40.5) 84 (44.2) 29 (15.3) 238 (62.6) 142 (37.4) Control 81 (42.6) 93 (48.9) 16 (08.4) 255 (67.1) 125 (32.9) rs3759915 CC CG GG 0.782 C G 0.467 Schizophrenia 55 (28.9) 87 (45.8) 48 (25.3) 197 (51.8) 183 (48.2) Control 60 (31.6) 87 (45.8) 43 (22.6) 207 (54.5) 173 (45.5) rs3759914 TT TC CC 0.099 T C 0.146 Schizophrenia 78 (41.1) 85 (44.7) 27 (14.2) 241 (63.4) 139 (36.6) Control 84 (44.2) 92 (48.4) 14 (07.4) 260 (68.4) 120 (31.6) SNP : single-nucleotide polymorphism
No Association between ST8SIA2 and Schizophrenia Yoo JH, et al Table 3. Results of association analyses under additive, dominant, recessive and co-dominant model assumptions SNP model rs3759916 rs3759915 rs3759914 Statistic p value Statistic p value Statistic p value Additive* 1.306 0.192 0.700 0.484 1.482 0.139 Dominant 0.098 0.755 0.200 0.655 0.269 0.604 Recessive 3.343 0.057 0.231 0.631 3.937 0.047 Co-dominant 4.315 0.116 0.492 0.782 4.621 0.099 * : Cochran-Armitage trend test was used to examine the additive effect of risk allele on schizophrenia, : chi-square test was used. SNP : single-nucleotide polymorphism Table 4. Estimated individual haplotype frequencies of ST8SIA2 Haplotype* Schizophrenia Frequency 배체중 1% 이상의빈도를보이는일배체에대한연합분석에 서도유의한결과는확인되지않았다 (Table 4). Control 본연구는한국인조현병환자및정상인을대상으로 ST8- SIA2 전사조절부위의 SNP 인 rs3759916, rs3759915 및 rs37-59914 에대하여조현병과의연합을탐색하였다. rs3759916 및 rs3759915 의분석에서는조현병과의유의한연합이관찰되지 않았으며, rs3759914 에서는경향성을확인할수있었으나 ( 열 성유전모델, p = 0.047), 다중검사오류를보정하였을때는 본연구에서설정한유의수준에도달하지못하였다. Individual p value TCT 0.510 0.544 0.346 CGC 0.357 0.315 0.219 TGT 0.116 0.127 0.656 * : Haplotypes with frequencies greater than 0.01 are shown, : Haplotype frequencies were estimated by the Haploview 4.2 ST8SIA2 유전자에대한연구는그수가많지않으나, 조현병 및양극성정동장애발병과관련된결과를꾸준히제시하고 있다. 먼저, ST8SIA2 유전자의결손은해마에서 infrapyramidal mossy fiber 의유도를방해하고, 이소성시냅스 (ectopic synapse) 를형성하게하는것으로알려져있다. 17) 그런데, 해마의이 상은조현병과양극성정동장애모두에서나타나는공통적인 특징으로, 21)22) 두질환의발병에 ST8SIA2 유전자가어떠한역 할을할가능성을시사한다. 또한, 조현병과양극성정동장애 환자를대상으로한일부광범위유전체연구에서도, ST8SIA2 가위치한 15q26 염색체좌에서의미있는결과가관찰되었다. Maziade 등 5) 와 Vazza 등 6) 은각각 Eastern Quebec 지역과이 탈리아 Chioggia 지역에서조현병또는양극성정동장애를가 진가계를대상으로광범위유전체연관연구를시행하여, 두 질환의공유염색체좌인 15q26 에위치한표지자가유의한 연관성을보이는것을밝혀냈다. Lee 등 23) 은중국인양극성정 동장애환자 1409 명과정상군 2000 명을대상으로광범위유전 체연합연구를시행하여 15q26에위치한 rs8040009에서의미있는연합을확인하였는데, 이 SNP은 ST8SIA2 안에위치하지는않으나가까운거리에위치한것으로알려졌다. 이러한결과로부터, ST8SIA2는인종적배경과관계없이조현병및양극성정동장애의발병에공통으로기여하는후보유전자일것으로추정된다. ST8SIA2와조현병과의관련성을규명하기위한일본및중국의연합연구에서도유의한결과가확인되었다. Arai 등 18) 은일본인조현병환자 188명과정상군 156명을대상으로하여 ST8SIA2 및 ST8SIA4에위치한총 21개의 SNPs과조현병의연합을탐색하였다. 그중 ST8SIA2 전사조절부위에위치한 rs3759916, rs3759914 에서의미있는대립유전자연합이확인되었으며, 유전자형분석에서도경계수준의연합경향이나타났다. 연관불균형블록에대해일배체분석을시행한결과, rs3759916-rs3759915-rs3759914 를포함하여, 5개의 SNPs으로구성된블록중 C-G-C-G-C 이정상군에서유의하게높게나타났고, T-G-T-G-C 일배체는환자군에서유의하게높은것으로나타났다. Tao 등 19) 은중국인조현병환자 643명과정상군 527명을대상으로 Arai 등 18) 의연구에서유의한결과를보인 SNPs을포함하여, ST8SIA2 유전자의 9개 SNPs을조사하였으며그중 rs3759915 가조현병과유의한연합을보이는것을보고하였다. 또한, C-G-T 염기서열로배열된일배체가정상군에서유의하게높게나타남을확인하였다. 하지만본연구에서는일본과중국의연구와는달리의미있는연합을확인하지못하였는데, 연구대상의대립유전자빈도 (allele frequency) 의차이가결과에영향을미쳤을가능성이있다. 특히 rs3759915 의 C 대립유전자빈도는본연구에서 53.2% 로나타났으나, 일본과중국의연구에서는각각 48.5%, 49.1% 로나타나차이를보이고있었다. 이러한대립유전자의차이는각연구마다대상군의수나인종적배경이다르다는점을고려해야할것으로생각된다. 본연구의제한점은다음과같다. 첫째, 본연구는유의한결과를제시한일본인대상연구 18) 에서와유사한 SNPs 을선정하였으며, 대상자수도유사한수준이었지만, 일반적인복합유전질환대상의연합연구에비해대상군수가적었던점을들수 journal.biolpsychiatry.or.kr 143
Korean J Biol Psychiatry 2012;19:140-145 있다. 현재까지의연구결과들에서, 조현병발병에는개별적으 로봐서는아주적은영향력을가진여러유전자변이가함께작 용할것으로생각되며, ST8SIA2 의 SNPs 또한그중하나로생 각된다. 따라서본연구의대상군수는충분한검증력을제공 하지못했을것으로생각된다. 특히, p < 0.05 수준의연합이시 사된 rs3759914 는사례수증가시다중검정오류를보정한후에 도연합의유의성이유지될가능성이있을것이다. 둘째, 정상 군의선정과정에서연령과성별등의변수를통제하지않아, 환 자군과정상군의평균연령에서통계적인차이가나타나고있 다. 또한대상군의평균연령을고려할때, 정상군에포함된대상 자의연령이일반적으로알려진조현병의초발연령을넘지않은 경우가포함되어있을것으로추정된다. 따라서, 정상군중에서도 조현병발병의유전적소인을가지고있을가능성을완전히배제 하기어렵다. 셋째, 본연구에서는 ST8SIA2 의일부 SNPs 만을분 석하였기때문에, 유전자내의다른 SNP 이조현병발병에미치 는영향을탐색할수없었다. 앞으로의연구에서는 ST8SIA2 의 유전자전역을대표할수있는 tag-snp 을선정하여조현병과 의연합을확인해볼필요가있을것이다. 본연구에서는한국인을대상으로조현병과 ST8SIA2 전사 조절부위 SNPs 와의연합을탐색하였다. 그결과, rs3759914 에서 연합이시사되었으나, 유의한수준의결과는발견하지못하였 다. 그러나 ST8SIA2 는그기능과기존의광범위유전체연구들 의결과들을고려하였을때, 복합유전질환인조현병의병태생 리와관련이있을것으로추정되는바, 향후충분한수의표본집 단을대상으로, ST8SIA2 내의다른 SNPs 을포함하여이유전자 의 경도효과 (minor effect) 를탐색하는연구가필요하겠다. 중심단어 :ST8SIA2 조현병 유전자다형성 연합. Acknowledgments 이연구는보건복지가족부보건의료연구개발사업중개연구센터 (A090096-0911-0000100) 연구비지원으로이루어짐. 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