SEARCH FOR DNA MARKERS LINKED TO MANIC DEPRESSIVE ILLNESS IN THE OLD ORDER AMISH

我们正在进行全基因组搜索，以确定包含与双相情感障碍(BPAD，躁郁症)相关基因的染色体区域。大约1%的人受到这种严重的复发性情绪障碍的困扰，未经治疗的BPAD患者有大约20%的自杀死亡风险。我们正在研究来自旧秩序阿米什人的几个大家庭，在那里，BPAD的发病率在几代人中非常高。在这些旧秩序阿米什家庭中，可能有更有限数量的不同基因导致情感障碍表型。除了其他已报道的与BPAD相关的基因(即与染色体4p、4q、11、12、18q、21、22和X)外，我们的结果表明，染色体6p SIBPAL(p&lt；0.0001)、染色体13 SIBPAL(p=0.0003)和染色体15 SIBPAL(p=0.0003)上的基因在增加双相情感障碍的易感性方面具有作用。此外，我们没有将全基因组搜索限制在确定BPAD的易感基因上，而是测试了这样的假设，即“保护性”等位基因可能有助于在这些“高风险”家庭中未受影响的家庭成员中没有精神疾病(即心理健康)。我们在染色体4p SIBPAL(p&lt；0.00001；GENEHUNTER NPL=3.8.8)和4Q SIBPAL(P&lt；0.001；GENEHUNTER NPL=4.7.)上发现了与精神健康相关的强有力的证据，这表明某些等位基因可以预防或改变BPAD的临床表现。对易感性和“保护性”等位基因的识别和表征应导致开发更合理和直接的方法来有效治疗情感障碍。

We are carrying out a genome-wide search to identify chromosome regions that contain genes involved in bipolar affective disorder (BPAD, manic depressive illness). Approximately one percent of the population is afflicted by this severe recurrent mood disorder and untreated patients with BPAD have an approximately 20% risk of death from suicide. We are studying several large families from the Old Order Amish population where there is a very high incidence of BPAD over several generations. In these Old Order Amish families there may be a more limited number of different genes contributing to the affective disorder phenotype. In addition to the other reported linkages for BPAD, (i.e. to chromosomes 4p, 4q, 11,12,18q, 21,22 and X), our results suggest that genes on chromosome 6p SIBPAL (p<0.0001), chromosome 13 SIBPAL (p=0.0003), and chromosome 15 SIBPAL (p=0.0003), have roles in increasing the susceptibility to bipolar affective disorder. Also, rather than limiting our genome-wide search to identifying susceptibility loci for BPAD, we tested the hypothesis that "protective" alleles may contribute to the absence of psychiatric illness (i.e., mental health "wellness") in unaffected family members in these "high risk" families. We found strong evidence for loci on chromosome 4p SIBPAL (p<0.00001; GENEHUNTER NPL=3.8) and 4q SIBPAL (p<0.001; GENEHUNTER NPL=4.7) that are linked to mental health wellness suggesting that certain alleles could prevent or modify the clinical manifestations of BPAD. The identification and characterization of susceptibility and "protective" alleles should lead to the development of more rational and direct approaches to effective therapy for affective disorders.