Narrowing the boundaries of the genetic architecture of schizophrenia.
Narrowing the boundaries of the genetic architecture of schizophrenia.
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DOI：
10.1093/schbul/sbp137
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发表时间：
2010-01
影响因子：
6.6
通讯作者：
Visscher PM
中科院分区：
文献类型：
--
作者：
Wray NR;Visscher PM
疾病的遗传结构包括遗传风险等位基因的数量、频率和效应大小，以及它们组合在一起的方式。在基因组学革命之前，精神分裂症潜在遗传结构的唯一线索来自亲属的复发风险和家庭内部的分离模式。从这些线索来看，非常简单的遗传结构可以被拒绝，但许多结构与观察到的家族数据一致。全基因组关联研究的新时代可以为精神分裂症的遗传结构提供进一步的线索。我们通过描述来探索遗传结构的模型，而不是通过支撑它们的数学。我们的结论是，新的全基因组数据使我们能够缩小与观察数据一致的遗传结构模型的边界。可以排除许多中等常见变异（相对风险>约为1.2）的遗传结构，但有证据表明，当前一代全基因组芯片确实标记了精神分裂症遗传变异的重要比例，潜在的因果变异将包括影响较小的常见变异以及影响较大的罕见变异。综上所述，这些观察结果表明，基因变异的总数非常大——大约有数千个。第一代研究已经产生了在不久的将来应该可以测试的假设，并将进一步缩小与经验数据一致的遗传结构的界限。
Genetic architecture of a disease comprises the number, frequency, and effect sizes of genetic risk alleles and the way in which they combine together. Before the genomic revolution, the only clue to underlying genetic architecture of schizophrenia came from the recurrence risks to relatives and the segregation patterns within families. From these clues, very simple genetic architectures could be rejected, but many architectures were consistent with the observed family data. The new era of genome-wide association studies can provide further clues to the genetic architecture of schizophrenia. We explore models of genetic architecture by description rather than the mathematics that underpins them. We conclude that the new genome-wide data allow us to narrow the boundaries on the models of genetic architecture that are consistent with the observed data. A genetic architecture of many common variants of moderate (relative risk > approximately 1.2) can be excluded, yet there is evidence that current generation genome-wide chips do tag an important proportion of the genetic variation for schizophrenia and that the underlying causal variants will include common variants of small effect as well as rarer variants of larger effect. Together, these observations imply that the total number of genetic variants is very large—of the order of thousands. The first generation of studies have generated hypotheses that should be testable in the near future and will further narrow the boundaries on genetic architectures that are consistent with empirical data.
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