GWAS란 무엇인가?
Association study는 연관분석으로, 관심을 가진 형질(phenotype)과 연관성을 갖는 유전적 위치를 찾는 분석방법을 말합니다. 특히, genome wide association study (GWAS)라는 전장 유전체 연관분석 방법이 잘 알려져 있습니다. 전장 유전체 연관분석은 모든 유전체 위치에 대해 연관분석을 수행하는 것을 말합니다.
GWAS는 일반적으로 관심 형질을 가진 집단(case)과 해당 형질을 갖지 않는 정상군(control), 두 집단의 유전정보를 얻은 후 서로 비교하여 control에 비해 case에서 더 많은 빈도를 보이는, 연관성을 갖는 유전자를 찾게 됩니다. 구체적으로는, 10만개에서 100만 개 이상의 SNP들을 마이크로어레이 실험을 통해서 개개인의 SNP 유전자형 (genotype)을 결정하고, 이 유전자형들이 질병이나 특정 표현형과 동시에 존재할 확률을 계산하여, 이들 중 유의성이 높게 나타난 SNP를 발굴하는 분석입니다.
GWAS의 분석을 이해하는데 필요한 개념으로 연관 불균형 (linkage disequilibrium, LD) 현상이 있습니다. 서로 거리가 가까운 유전자들은 거리가 먼 유전자들에 비해 생식 세포 분열 과정에서 유전자 재배열이 일어나지 않고 함께 유전되는 현상입니다. 이렇게 함께 유전되는 단위를 LD block또는 haplotype이라고 합니다.
GWAS 분석 결과는 의미 있는 염색체 내의 위치가 통계적 확률값으로 나타나는데, 주로 맨하탄 플롯 (Manhattan plot)으로 제시됩니다. 의미있는 시그널이 마치 뉴욕 맨하탄 가에 위치한 고층 빌딩처럼 보여서 붙여진 이름입니다.
GWAS에서 Manhattan plot의 해석
Manhattan plot은 가로축에는 유전체상의 위치를, 세로축에는 해당 위치의 통계적 유의성을 나타내는 -log10(P-value)를 표시합니다. 각 점은 특정 유전자 변이와 관심 특성 간의 연관성을 나타내며, 높은 P-value 값은 높은 연관성을 나타냅니다.
Manhattan plot의 주요 목적은 유전체상에서 특성과 관련된 유의미한 유전자 변이를 식별하는 것입니다. 높은 연관성을 가진 변이는 세로축에서 높은 값을 가집니다. 유의미한 연관성을 가진 변이들이 발견되면, 해당 변이들이 속한 유전자들의 기능을 연구하여 특성과의 관련성을 이해하는 것이 중요합니다.
유의미한 연관성을 가진 변이들 중에서도, 효과 크기(effect size)를 고려하여 특성에 미치는 영향력이 큰 변이를 찾는 것이 중요합니다. 효과 크기는 해당 변이가 특성에 얼마나 큰 영향을 미치는지를 나타냅니다. 높은 효과 크기를 가진 변이는 더 중요한 연구 대상이 될 수 있습니다.
복수의 연관성이 있는 경우, 여러 변이들이 독립적으로 또는 상호 작용하며 특성에 영향을 줄 수 있습니다. 이 경우, 해당 변이들 간의 상호 작용과 통합적인 효과를 이해하기 위해 추가 연구가 필요합니다.
또한, 특성 발현에는 유전자 변이 외에도 환경 요인, 유전자 조절 요소 등 다양한 요소가 영향을 미칩니다. Manhattan plot은 유전자 변이와 특성 간의 연관성만을 고려하기 때문에, 이러한 요소들의 영향을 반영하지 못할 수 있습니다.
GWAS에서 다루는 통계는?
GWAS에서 다루는 형질은 보통 범주형 자료이기 때문에 주로 로지스틱 회귀분석(logistic regression analysis)의 통계방법으로 데이터를 분석하게 됩니다. 그런데, GWAS에서는 수십만 개의 유전 변이를 이용하여 하나의 표현형에 대해 통계적 시험을 하기 때문에 다중비교의 오류가 생기게 됩니다. 다중검정의 경우에는 일반적으로 사용하는 p value cutoff인 0.05가 아니라 좀 더 엄격한 기준으로 검정해야 하는데, Bonferroni correction이나 FDR correction이라는 통계적 보정 기법을 이용해야 합니다. 이렇게 다중비교의 오류를 보정한 p value를 corrected p라고 합니다.
GWAS 결과 해석 시 고려해야 할 요소들
GWAS 분석은 대량의 유전자 정보를 처리하므로 결과의 해석에는 주의가 필요합니다. 예를 들어, 유전자와 질병 사이의 연관성을 분석할 때 발견된 결과가 유의미하다고 해서 반드시 원인-결과 관계를 나타내지는 않습니다. 이를 ‘연관성과 원인관계의 차이’라고 합니다.
또한, GWAS 분석 결과가 유의미하더라도 연구 대상 집단이 어떤 특징을 가지고 있는지, 연구 설계와 분석 방법이 어떤 한계점을 가지는지 등 다양한 요인들이 결과 해석에 영향을 미칩니다. 따라서 GWAS 분석 결과를 정확하게 해석하기 위해서는 다양한 요소들을 고려해야 합니다.
인과관계 확인을 위해서는 더 많은 환자군(replication cohort)에서 확인해야하고, 추가적인 동물 및 세포 실험을 거쳐야 한다. 이런 과정을 거친 후, 인과관계가 밝혀진 결과들은 GWAS Catalog에 저장됩니다.
GWAS 분석 이외의 유전체 연관 분석 방법
GWAS 분석 이외에도 유전체 연관 분석을 수행할 수 있는 다양한 방법들이 있습니다. 대표적으로는 ‘전사체 분석(transcriptome analysis)’과 ‘유전체 염기서열 분석(whole genome sequencing)’이 있습니다.
전사체 분석은 RNA를 분석하여 유전자 발현 패턴과 그에 따른 질병과의 연관성을 파악하는 방법입니다. 이를 통해 특정 유전자가 발현되지 않는 경우나 발현 수준이 높은 경우와 질병 사이의 연관성을 찾아낼 수 있습니다.
유전체 염기서열 분석은 GWAS 분석과는 달리 전체 유전체의 염기서열을 분석하는 방법입니다. 이를 통해 특정 지점에서의 돌연변이, 즉 DNA 염기서열의 변화와 질병 사이의 연관성을 파악할 수 있습니다.
GWAS 분석 결과를 활용한 의학 분야의 발전
GWAS 분석 결과는 의학 분야에서 다양하게 활용되고 있습니다. 예를 들어, 각종 질환의 유전적 원인을 찾아내는 데에 활용될 수 있습니다. 특히, GWAS는 염기서열의 다양성을 고려하여 질병과 연관된 염기 변이를 찾아낼 수 있으므로, 이전 연구에서 찾을 수 없었던 새로운 질병 유전자를 찾아낼 수 있는 장점이 있습니다. 이러한 정보를 기반으로 개발된 예방, 진단, 치료법 등은 개인 맞춤형 의학의 발전에 큰 역할을 할 것으로 기대됩니다.
또한, GWAS 분석 결과는 약물개발에도 활용됩니다. 예를 들어, 어떤 약물이 특정 질환 유전자와 관련이 있는 경우, 해당 약물을 선택하는 것이 해당 질환을 치료하는 데 효과적일 가능성이 높아집니다. 이를 통해 약물 개발 시간과 비용을 줄일 수 있습니다.
GWAS 분석 결과는 또한 질병 예방에도 활용될 수 있습니다. 예를 들어, 특정 질병과 연관된 유전자가 밝혀졌을 경우, 해당 질병을 예방하기 위해 유전자 변이를 가진 사람들은 더욱 예방에 신경을 써야 한다는 경각심을 갖게 됩니다. 이를 통해 개인 맞춤형 예방과 치료를 실현할 수 있습니다.
GWAS 분석 결과는 또한 연구분야에도 큰 영향을 미치고 있습니다. 예를 들어, GWAS 분석 결과를 활용한 다양한 연구들이 진행되고 있습니다. 이를 통해 기존의 학문적 지식을 보완하고 새로운 진전을 이루는 데에 기여하고 있습니다.
맨하탄플롯 재미있네요~ 임상에서 어떻게 이용되나요?
GWAS 분석으로 특정 유전자의 변이가 질병과 확실한 인과관계가 있다는 것이 밝혀지게 되면 해당 유전자에 변이가 있는지 검사하여 질병의 진단 및 예방에 활용할 수 있겠죠? ㅎㅎ
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