Genome-wide approaches to schizophrenia.
Genome-wide approaches to schizophrenia.
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DOI：
10.1016/j.brainresbull.2010.04.009
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发表时间：
2010-09-30
影响因子：
3.8
通讯作者：
Gejman PV
中科院分区：
文献类型：
--
作者：
Duan J;Sanders AR;Gejman PV
精神分裂症（SZ）是一种常见的、严重的精神疾病，具有环境和遗传双重危险因素，遗传度高。经过20多年的分子遗传学研究，新的分子策略，主要是全基因组关联研究（GWAS），已经产生了重大的实际进展。这些新数据为以下方面提供了证据：1）许多具有常见多态性的染色体区域显示出与SZ的全基因组关联（主要组织相容性复合体，MHC，6p 22-p21; 18q21.2;和2q32.1区域）。相关的等位基因呈现小的优势比（风险变异存在于病例与对照组的优势比），并表明SZ的基因调控机制的致病性参与。2)多基因遗传。3)涉及罕见（<1%）和大（> 100 kb）拷贝数变异（CNV）。4)SZ与自闭症和双相情感障碍（BP）的遗传重叠挑战了经典的临床分类。大多数新的SZ发现（染色体区域和基因）都产生了新的生物学线索。然而，这些新发现仍然需要转化为对潜在生物学和因果机制的更好理解。此外，相当多的遗传力仍然无法解释（缺失遗传力）。罕见变异的深度重测序和系统生物学方法（例如，整合DNA序列和功能数据），预计将进一步提高我们对SZ的遗传结构及其基础生物学的理解。
Schizophrenia (SZ) is a common and severe psychiatric disorder with both environmental and genetic risk factors, and a high heritability. After over 20 years of molecular genetics research, new molecular strategies, primarily genome-wide association studies (GWAS), have generated major tangible progress. This new data provides evidence for: 1) A number of chromosomal regions with common polymorphisms showing genome-wide association with SZ (the major histocompatibility complex, MHC, region at 6p22-p21; 18q21.2; and 2q32.1). The associated alleles present small odds ratios (the odds of a risk variant being present in cases versus controls) and suggest causative involvement of gene regulatory mechanisms in SZ. 2) Polygenic inheritance. 3) Involvement of rare (<1%) and large (>100kb) copy number variants (CNVs). 4) A genetic overlap of SZ with autism and with bipolar disorder (BP) challenging the classical clinical classifications. Most new SZ findings (chromosomal regions and genes) have generated new biological leads. These new findings, however, still need to be translated into a better understanding of the underlying biology and into causal mechanisms. Furthermore, a considerable amount of heritability still remains unexplained (missing heritability). Deep resequencing for rare variants and system biology approaches (e.g., integrating DNA sequence and functional data) are expected to further improve our understanding of the genetic architecture of SZ and its underlying biology.
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