Candidate Gene Analysis of Mood Disorder, including the IMPA2 Gene

在我们寻找18号染色体短臂上情感障碍的候选基因时，我们克隆了IMPA 2，一种以前未报道的肌醇单磷酸酶，定位于18p11.2。最近，连锁分析和基于家系的关联研究均显示GOLF与精神分裂症相关。有趣的是，IMPA 2的位置非常接近GOLF（100 kb）。为了筛选IMPA 2基因中的突变，我们确定了基因组结构并鉴定了10种不同的多态性：（1）-466G>A（启动子），（2）-219C>T（启动子），（3）58 G>A（外显子1），（4）IVS 1 - 15 G>A，（5）401 T>C（Leu 53 Leu）（外显子2），（6）468 C>T（His 76 tyr）（外显子2），（7）IVS 5 +13- 14 insA（内含子5），（8）776 T>C（Arg 178 Arg），（9）800 C>T（Phe 186 Phe）（外显子6），（10）1079 C>G（Thr 279 Thr）（外显子8）。在本研究中，我们进行了关联测试的日本队列，其中包括302精神分裂症，212例情感障碍和308匹配的控制。在这些样品中未检测到错义突变（His 76 Tyr）。我们对三种不同的多态性（3）、（4）和（9）进行了基因分型。没有发现这些与情绪障碍有关。相反，在精神分裂症样本中，所有多态性均存在显著的基因型和/或等位基因相关性。这些结果表明，IMPA 2基因可能参与了精神分裂症在日本人口的发病机制。由于可能的功能多态性仅存在于启动子区域，因此除了通过进一步的遗传分析来细化关键区域之外，检查由这些变体诱导的转录结果将是重要的。

In our search for candidate genes for affective disorder on the short arm of chromosome 18, we cloned IMPA2, a previously unreported myo-inositol monophosphatase, that mapped to 18p11.2. Recently, a marker GOLF was shown to be linked to schizophrenia by both linkage analysis and family-based association study. Interestingly the location of the IMPA2 is very close to the GOLF(100kb). For the screening of mutations in the IMPA2 gene, we have determined the genomic structure and identified 10 different polymorphisms: (1)-466G>A (promoter), (2)-219C>T (promoter), (3)58G>A (exon 1), (4)IVS1-15G>A, (5)401T>C (Leu53Leu) (exon 2), (6)468C>T (His76tyr) (exon 2), (7)IVS5+13-14insA (intron 5), (8)776T>C (Arg178Arg), (9)800C>T (Phe186Phe) (exon6), (10)1079C>G (Thr279Thr) (exon 8). In the present study, we performed association tests on Japanese cohorts that included 302 schizophrenics, 212 patients with affective disorder and 308 matched controls. The missense mutation (His76Tyr) was not detected in these samples. We genotyped the three different polymorphisms, (3), (4) and (9). None of these were found to be associated with mood disorders. In contrast, in the schizophrenia sample there were significant genotypic and/or allelic associations regarding all the polymorphisms. These results suggest that the IMPA2 gene may be involved in a pathogenesis of schizophrenia in Japanese population. Since possible functional polymorphisms are only those which exist in the promoter region, it will be important to examine transcriptional consequences induced by those variants, in addition to refine the critical region by further genetic analysis.