한국인 자폐스펙트럼장애에서 Glutamate Receptor, Ionotropic, N-methyl-D-Aspartate 2B (GRIN2B) 유전자 다형성 ？ 가족기반연구
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목적: 본 연구의 목적은 자폐스펙트럼장애를 가진 아동들과 그 부모로 이루어진 trio를 대상으로 이 장애와 NMDA 수용체 유전자, 그 가운데 GRIN2B 유전자와의 관련성을 규명하고자 하는 것이다. 방법: 발달지연을 주소로 가천의대 길병원과 경상대학교병원 소아정신과 외래를 내원한 아동을 선별 대상으로 하였다. DSM-IV 진단체계를 이용하여 2명의 소아정신과 의사가 자폐 스펙트럼 장애로 진단한 아동이 일차적인 연구 대상으로 선별되었다. 선별된 아동과 부모들에게는 한국판 자폐증 진단 관찰 스케줄(Autism Diagnostic Observation Schedule, 이하 ADOS) 및 자폐증 진단 면담 개정판 (Autism Diagnostic Interview Revised, 이하 ADI-R)를 실시하였다. PCR-RFLP법을 이용, GRIN2B 유전자에서 모두 4개의 단일 염기 다형성을 분석하였다(rs7301328, rs1806201, rs1805247, rs1805502). 각각의 SNPs에 대한 allelic association 을 평가하기 위하여 TDT 방법이 시행되었으며, 이를 통해 자폐장애 아동이 부모로부터 후보유전자의 특정 alleles들을 유의하게 더 많이 전달받았는지의 여부를 관찰한 뒤 McNemar chi-square test (df=1)에 의거하여 분석하였다. 결과: (1) 연구 대상군의 특성: 총 126명의 자폐 스펙트럼장애 아동과 그들의 생물학적 부모가 최종 분석 대상에 포함되었다. 전체 대상자 중 109명 (86.5%)이 남아였으며 여아는 17명 (13.5%)으로, 남아 대 여아의 비율은 6.41:1이었다. 대상군의 진단 분포는 자폐장애 107 명(85.1%), 달리 분류되지 않는 전반적 발달장애(PDD, NOS) 17명 (13.5%), 아스퍼거 씨 장애(Asperger’s disorder) 2명 (1.6%)이었다. 대상군 아동의 평균 연령은 71.9±31.6 개월 (range: 26~185개월)이었으며 한국판 사회성숙도 검사로 측정된 평균 사회지수(Social Quotient)는 61.2±20.6 (range: 23.1~126), 측정 가능한 아동들의 평균 지능은 65.0±27.7 (range: 25~126)이었다. K-CARS 점수는 31.5±5.4 (range 18.5~46)로 나타났다. (2) 유전자 분석: 분석한 GRIN2B 유전자의 4개 SNPs 가운데 하나의 SNP (rs1805247)에서 의미 있는 allelic transmission의 차이를 보였다. 이 SNP에서 transmission ratio (transmitted alleles/non-transmitted alleles)는 A allele과 G allele에서 각각 2.03과 .49로, A allele이 G allele에 비해 부모로부터 환자군에게 더 빈번하게 전달(preferential transmission) 되었음이 확인되었다(TDT χ2 = 12.89, p=.0003). 이는 Bonferroni correction 후에도 여전히 유의미한 수준을 유지하였다 (p=.0009). 기타 3개의 SNP (rs7301328, rs1806201, rs1805502) 들에서는 의미 있는 transmission의 차이가 나타나지 않았다 (p<.05).결론: 본 연구에서 GRIN2B 유전자의 단일유전자 다형성과 자폐스펙트럼장애 사이에 유의한 연관성을 보였다. 이는 glutamate NMDA 2B수용체 유전자가 이 질환의 발생에 관여할 가능성을 시사하는 것이라 생각된다.
Abstract
Objectives: Autism is a complex neurodevelopmental spectrum disorder with a strong genetic component. Previous neurochemical and genetic studies suggested the possible involvement of glutamate N-methyl-D-aspartate (NMDA) receptor in autism. The aim of study was to investigate the association between the NMDA2B receptor gene (GRIN2B) and autism spectrum disorders (ASD) in the Korean population. Methods: The patients with ASD were diagnosed with Autism Diagnostic Interview – Revised and Autism Diagnostic Observation Schedule based on DSM-IV diagnostic classification. The present study was conducted with the detection of four single nucleotide polymorphisms (SNPs) in GRIK2 and family-based association analysis of the single nucleotide polymorphisms in Korean ASD trios using transmission disequilibrium test (TDT). Results: One hundred twenty six patients with ASD and their biological parents were analyzed. 86.5% were male and 85.1% were diagnosed as autistic disorder. The mean age was 71.9±31.6 months (range: 26~185 months). We found that rs1805247 showed significantly preferential transmission (TDT χ2 = 12.8, p < 0.001) in ASD. Conclusion: One SNP in GRIN2B gene was significantly associated with ASD in the Korean population. This result suggests the possible involvement of glutamate NMDA receptor gene in the development of ASD.
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