Cannon Tyrone D, Thompson Paul M, van Erp Theo G M, Huttunen Matti, Lonnqvist Jouko, Kaprio Jaakko, Toga Arthur W
Department of Psychology, UCLA, Los Angeles, CA 90095, USA.
Neuroinformatics. 2006 Winter;4(1):5-19. doi: 10.1385/NI:4:1:5.
There is an urgent need to decipher the complex nature of genotype-phenotype relationships within the multiple dimensions of brain structure and function that are compromised in neuropsychiatric syndromes such as schizophrenia. Doing so requires sophisticated methodologies to represent population variability in neural traits and to probe their heritable and molecular genetic bases. We have recently developed and applied computational algorithms to map the heritability of, as well as genetic linkage and association to, neural features encoded using brain imaging in the context of three-dimensional (3D), populationbased, statistical brain atlases. One set of algorithms builds on our prior work using classical twin study methods to estimate heritability by fitting biometrical models for additive genetic, unique, and common environmental influences. Another set of algorithms performs regression-based (Haseman-Elston) identical-bydescent linkage analysis and genetic association analysis of DNA polymorphisms in relation to neural traits of interest in the same 3D population-based brain atlas format. We demonstrate these approaches using samples of healthy monozygotic (MZ) and dizygotic (DZ) twin pairs, as well as MZ and DZ twin pairs discordant for schizophrenia, but the methods can be generalized to other classes of relatives and to other diseases. The results confirm prior evidence of genetic influences on gray matter density in frontal brain regions. They also provide converging evidence that the chromosome 1q42 region is relevant to schizophrenia by demonstrating linkage and association of markers of the Transelin-Associated-Factor-X and Disrupted-In- Schizophrenia-1 genes with prefrontal cortical gray matter deficits in twins discordant for schizophrenia.
迫切需要解读神经精神综合征(如精神分裂症)中受损的大脑结构和功能多维度内基因型-表型关系的复杂本质。要做到这一点,需要复杂的方法来表征神经特征的群体变异性,并探究其遗传和分子遗传基础。我们最近开发并应用了计算算法,以在基于群体的三维(3D)统计脑图谱的背景下,绘制使用脑成像编码的神经特征的遗传力以及遗传连锁和关联。一组算法建立在我们之前的工作基础上,使用经典双生子研究方法,通过拟合用于加性遗传、独特和共同环境影响的生物统计学模型来估计遗传力。另一组算法在相同的基于3D群体的脑图谱格式中,对与感兴趣的神经特征相关的DNA多态性进行基于回归的(哈斯曼-埃尔斯顿)同型合子连锁分析和遗传关联分析。我们使用健康的同卵(MZ)和异卵(DZ)双生子对样本,以及患精神分裂症的MZ和DZ双生子对来展示这些方法,但这些方法可以推广到其他亲属类别和其他疾病。结果证实了先前关于遗传对额叶脑区灰质密度有影响的证据。它们还提供了趋同证据,表明1q42染色体区域与精神分裂症相关,通过证明与精神分裂症不一致的双生子中,转硒蛋白相关因子X和精神分裂症破坏基因1的标记与前额叶皮质灰质缺陷存在连锁和关联。