Carrera Noa, Sanjuán Julio, Moltó María Dolores, Carracedo Angel, Costas Javier
Fundación Pública Galega de Medicina Xenómica (FPGMX), University of Santiago Hospital Complex, Santiago de Compostela, Spain.
Am J Med Genet B Neuropsychiatr Genet. 2009 Apr 5;150B(3):369-74. doi: 10.1002/ajmg.b.30823.
The ancestral susceptibility hypothesis has been proposed to explain the existence of susceptibility alleles to common diseases. Some ancestral alleles, reflecting ancient adaptations, may be poorly adapted to the more contemporary environmental conditions giving rise to an increased risk to suffer some common disorders. In order to test this hypothesis in schizophrenia, we focused on the monoamine oxidase B gene (MAOB). This gene is involved in deamination of several monoamines, including both xenobiotic amines present in several foods, as well as neurotransmitters such as dopamine. In addition, preliminary analysis based on phase I HapMap data suggested that recent natural selection has acted on this locus. We further explored the existence of this recent positive selection using a test based on extension of linkage disequilibrium (LD) to large distance at the specific selected haplotype taking data from HapMap phase II, and searched for association of the ancestral haplotypes with schizophrenia in a sample of 532 schizophrenic patients and 597 controls from Spain. Our analysis suggested the existence of a haplotype of MAOB subject to recent selection. In agreement with the ancestral susceptibility hypothesis, the ancestral haplotypes were significantly over-represented in patients (P = 0.047). These haplotypes conferred an increased risk to schizophrenia, restricted to males (P = 0.024, OR = 1.41, 95% CI 1.01-1.90). Thus, pending on replication studies, MAOB seems to fit the ancestral susceptibility model, validating a new strategy to search for common schizophrenia susceptibility genes by focusing in those functional candidate genes subject to recent positive selection.
为了解释常见疾病易感性等位基因的存在，人们提出了祖先易感性假说。一些反映古代适应性的祖先等位基因，可能不太适应现代环境条件，从而增加了患某些常见疾病的风险。为了在精神分裂症中验证这一假说，我们聚焦于单胺氧化酶B基因（MAOB）。该基因参与多种单胺的脱氨基作用，这些单胺包括几种食物中含有的外源性胺以及多巴胺等神经递质。此外，基于国际人类基因组单体型图计划（HapMap）一期数据的初步分析表明，近期自然选择作用于该基因座。我们利用基于连锁不平衡（LD）扩展到特定选择单倍型上远距离的检验方法，采用来自HapMap二期的数据，进一步探究这种近期正向选择的存在，并在来自西班牙的532例精神分裂症患者和597例对照样本中，研究祖先单倍型与精神分裂症的关联性。我们的分析表明存在一种受近期选择的MAOB单倍型。与祖先易感性假说一致，祖先单倍型在患者中显著过度富集（P = 0.047）。这些单倍型增加了患精神分裂症的风险，且仅限于男性（P = 0.024，比值比[OR]=1.41，95%置信区间[CI]为1.01 - 1.90）。因此，有待重复研究验证，MAOB似乎符合祖先易感性模型，这验证了一种通过聚焦于那些受近期正向选择的功能候选基因来寻找常见精神分裂症易感基因的新策略。
