Genome-Wide Association Study in Bipolar Patients Stratified by Co-Morbidity
Genome-Wide Association Study in Bipolar Patients Stratified by Co-Morbidity
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DOI：
10.1371/journal.pone.0028477
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发表时间：
2011-12-21
期刊：
影响因子：
3.7
通讯作者：
Muthen, Bengt O.
中科院分区：
文献类型：
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作者：
Kerner, Berit;Lambert, Christophe G.;Muthen, Bengt O.
背景：双相情感障碍是一种具有高遗传性的严重精神疾病。共病的条件是常见的，可能会定义潜在的亚组的患者更同质的遗传风险factors.Methodology：在高加索GAIN双相情感障碍样本的1000例和1034对照，我们测试了单核苷酸多态性与共病定义的患者亚组的关联。双相情感障碍伴精神病和/或物质滥用而无酒精依赖与染色体6 q27上磷酸二酯酶10A（PDE 10A）基因附近的罕见变异rs 1039002相关（p = 1.7x10（-8））。PDE 10A与精神病的病理生理学有关。编码蛋白的拮抗剂目前正在临床测试中。另一个罕见的变异体rs 12563333（p = 5.9x10（-8））位于染色体1 q41上，靠近MAP/微管亲和力调节激酶1（MARK 1）基因，在该亚组中接近全基因组水平的显著性。病例中存在次要等位基因的纯合子，而对照组中不存在。双相情感障碍伴酒精依赖和其他共病与染色体3p26.3上的SNP rs 2727943（p = 3.3x10（-8））相关，该SNP位于基因contactin-4前体（BIG-2）和contactin 6（CNTN 6）之间。所有这三种关联都是在隐性遗传模型下发现的。双相情感障碍与合并症可能性低的患者并未表现出显着的相关性。结论：将双相情感障碍概念化为一种与合并症相关的异质性障碍可能有助于识别遗传风险等位基因。罕见的变异可能有助于双相情感障碍的易感性。
Background: Bipolar disorder is a severe psychiatric disorder with high heritability. Co-morbid conditions are common and might define latent subgroups of patients that are more homogeneous with respect to genetic risk factors.Methodology: In the Caucasian GAIN bipolar disorder sample of 1000 cases and 1034 controls, we tested the association of single nucleotide polymorphisms with patient subgroups defined by co-morbidity.Results: Bipolar disorder with psychosis and/or substance abuse in the absence of alcohol dependence was associated with the rare variant rs1039002 in the vicinity of the gene phosphodiesterase 10A (PDE10A) on chromosome 6q27 (p = 1.7x10(-8)). PDE10A has been implicated in the pathophysiology of psychosis. Antagonists to the encoded protein are currently in clinical testing. Another rare variant, rs12563333 (p = 5.9x10(-8)) on chromosome 1q41 close to the MAP/microtubule affinity-regulating kinase 1 (MARK1) gene, approached the genome-wide level of significance in this subgroup. Homozygotes for the minor allele were present in cases and absent in controls. Bipolar disorder with alcohol dependence and other co-morbidities was associated with SNP rs2727943 (p = 3.3x10(-8)) on chromosome 3p26.3 located between the genes contactin-4 precursor (BIG-2) and contactin 6 (CNTN6). All three associations were found under the recessive genetic model. Bipolar disorder with low probability of co-morbid conditions did not show significant associations.Conclusion: Conceptualizing bipolar disorder as a heterogeneous disorder with regard to co-morbid conditions might facilitate the identification of genetic risk alleles. Rare variants might contribute to the susceptibility to bipolar disorder.