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

我们正在进行一项全基因组搜索，以确定染色体区域包含基因参与双相情感障碍（BPAD，躁狂抑郁症）。 大约百分之一的人口患有这种严重的复发性情绪障碍，未经治疗的BPAD患者有大约20%的自杀死亡风险。 我们正在研究几个来自旧秩序阿米什人的大家庭，那里的几代人中BPAD的发病率非常高。 在这些旧秩序阿米什家庭可能有一个更有限的数量不同的基因有助于情感障碍的表型。除了其他报道的BPAD连锁（即与染色体4p，4 q，11，12，18 q，21，22和X），我们的研究结果表明，染色体6p SIBPAL（p<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中起作用。 此外，我们没有将我们的全基因组搜索限制在鉴定BPAD的易感基因座上，而是测试了“保护性”等位基因可能有助于不存在精神疾病的假设（即，精神健康“健康”）在这些“高风险”家庭中未受影响的家庭成员。 我们发现了染色体4p SIBPAL（p<0.00001; GENEHUNTER NPL=3.8）和4 q SIBPAL（p<0.001; GENEHUNTER NPL=4.7）上与精神健康相关的基因座的强有力证据，表明某些等位基因可以预防或改变BPAD的临床表现。 易感性和“保护性”等位基因的鉴定和表征应导致情感障碍的有效治疗更合理和直接的方法的发展。

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.