Laboratory of Neuro Imaging, David Geffen School of Medicine, University of California, Los Angeles, California, USA.
Nat Genet. 2012 Apr 15;44(5):552-61. doi: 10.1038/ng.2250.
Identifying genetic variants influencing human brain structures may reveal new biological mechanisms underlying cognition and neuropsychiatric illness. The volume of the hippocampus is a biomarker of incipient Alzheimer's disease and is reduced in schizophrenia, major depression and mesial temporal lobe epilepsy. Whereas many brain imaging phenotypes are highly heritable, identifying and replicating genetic influences has been difficult, as small effects and the high costs of magnetic resonance imaging (MRI) have led to underpowered studies. Here we report genome-wide association meta-analyses and replication for mean bilateral hippocampal, total brain and intracranial volumes from a large multinational consortium. The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 × 10(-16)) and the expression levels of the positional candidate gene TESC in brain tissue. Additionally, rs10784502, located within HMGA2, was associated with intracranial volume (12q14.3; N = 15,782; P = 1.12 × 10(-12)). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 × 10(-7)).
鉴定影响人类大脑结构的遗传变异可能揭示认知和神经精神疾病的新生物学机制。海马体体积是阿尔茨海默病早期的生物标志物，在精神分裂症、重度抑郁症和内侧颞叶癫痫中减少。虽然许多脑成像表型具有高度遗传性，但识别和复制遗传影响一直很困难，因为小效应和磁共振成像（MRI）的高成本导致研究力度不足。在这里，我们报告了来自一个大型跨国联盟的平均双侧海马体、总脑和颅内体积的全基因组关联荟萃分析和复制。位于 12q24.22 上的基因间变异 rs7294919 与海马体体积（N = 21151；P = 6.70 × 10(-16)) 和脑组织中位置候选基因 TESC 的表达水平相关。此外，位于 HMGA2 内的 rs10784502 与颅内体积（N = 15782；P = 1.12 × 10(-12)) 相关。我们还在 DDR2 内的 rs10494373 处发现了与总脑体积的关联（1q23.3；N = 6500；P = 5.81 × 10(-7))。
