Nassan Malik, Li Qingqin, Croarkin Paul E, Chen Wenan, Colby Colin L, Veldic Marin, McElroy Susan L, Jenkins Gregory D, Ryu Euijung, Cunningham Julie M, Leboyer Marion, Frye Mark A, Biernacka Joanna M
Department of Psychiatry & Psychology, Mayo Clinic Depression Center, Mayo Clinic, Rochester, MN, United States.
Janssen Research & Development, LLC, Titusville, NJ, United States.
J Affect Disord. 2017 Jan 15;208:120-129. doi: 10.1016/j.jad.2016.09.049. Epub 2016 Sep 30.
Although multiple genes have been implicated in bipolar disorder (BD), they explain only a small proportion of its heritability. Identifying additional BD risk variants may be impaired by phenotypic heterogeneity, which is usually not taken into account in genome-wide association studies (GWAS). BD with early age at onset is a more homogeneous familial form of the disorder associated with greater symptom severity.
We conducted a GWAS of early-onset BD (onset of mania/hypomania ≤19 years old) in a discovery sample of 419 cases and 1034 controls and a replication sample of 181 cases and 777 controls. These two samples were meta-analyzed, followed by replication of one signal in a third independent sample of 141 cases and 746 controls.
No single nucleotide polymorphism (SNP) associations were genome-wide significant in the discovery sample. Of the top 15 SNPs in the discovery analysis, rs114034759 in the muskelin (MKLN1) gene was nominally significant in the replication analysis, and was among the top associations in the meta-analysis (p=2.63E-06, OR=1.9). In the third sample, this SNP was again associated with early-onset BD (p=0.036, OR=1.6). Gene expression analysis showed that the rs114034759 risk allele is associated with decreased hippocampal MKLN1 expression.
The sample sizes of the early-onset BD subgroups were relatively small.
Our results suggest MKLN1 is associated with early-onset BD. MKLN1 regulates cellular trafficking of GABA-A receptors, which is involved in synaptic transmission and plasticity, and is implicated in the mechanism of action of a group of antiepileptic mood stabilizers. These results therefore indicate that GABAergic neurotransmission may be implicated in early-onset BD. We propose that an increase in GABA-A receptors in the hippocampus in BD patients due to lower MKLN1 expression might increase the excitability during the GABA-excited early phase of young neurons, leading to an increased risk of developing a manic/hypomanic episode. Further studies are needed to test this model.
尽管多个基因与双相情感障碍（BD）有关，但它们仅解释了其遗传度的一小部分。识别其他BD风险变异可能会受到表型异质性的影响，而全基因组关联研究（GWAS）通常未考虑这一点。早发型BD是该疾病中一种更具同质性的家族形式，与更严重的症状相关。
我们在一个包含419例病例和1034例对照的发现样本以及一个包含181例病例和777例对照的复制样本中，对早发型BD（躁狂/轻躁狂发作年龄≤19岁）进行了GWAS。对这两个样本进行了荟萃分析，随后在第三个包含141例病例和746例对照的独立样本中对一个信号进行了复制。
在发现样本中，没有单核苷酸多态性（SNP）关联达到全基因组显著性。在发现分析的前15个SNP中，肌肉素（MKLN1）基因中的rs114034759在复制分析中具有名义上的显著性，并且在荟萃分析中是顶级关联之一（p = 2.63E - 06，OR = 1.9）。在第三个样本中，该SNP再次与早发型BD相关（p = 0.036，OR = 1.6）。基因表达分析表明，rs114034759风险等位基因与海马体中MKLN1表达降低相关。
早发型BD亚组的样本量相对较小。
我们的结果表明MKLN1与早发型BD相关。MKLN1调节GABA - A受体的细胞转运，这参与突触传递和可塑性，并与一组抗癫痫心境稳定剂的作用机制有关。因此，这些结果表明GABA能神经传递可能与早发型BD有关。我们提出，由于MKLN1表达降低，BD患者海马体中GABA - A受体增加可能会增加年轻神经元在GABA兴奋早期的兴奋性，从而导致发生躁狂/轻躁狂发作的风险增加。需要进一步的研究来验证这个模型。
