Bulayeva Kazima, Lencz Todd, Glatt Stephen, Takumi Toru, Gurgenova Farida, Kawakami Hideshi, Bulayev Oleg
Dept. of Population Genetics, N.I. Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia.
Turk Psikiyatri Derg. 2012 Fall;23(3):161-70.
The purpose of this study was to determine the molecular epidemiology of early onset major depressive disorder (MDD) in genetic isolates of the Caucasus Dagestan indigenous ethnic populations using molecular and statistical population-genetic approaches.
Two multigenerational pedigrees from two diverse remote highland isolates with aggregation of early onset MDD were ascertained within our long-term research program titled 'Dagestan Genetic Heritage, DGH'. The first isolate included 48 cases of MDD (19 living) with 11 suicides committed, and the second included 60 MDD cases (30 living) with 12 suicides committed. The phenotypes of the affected family members were determined using a database containing diagnoses from a regional psychiatric hospital and through our own clinical examinations, which were based on a Russian translation of DIGS software based on the DSM-IV criteria . A 10 cM genomic scan (Weber/CHLC 9.0 STRs) of the 64 affected and non-affected members of the pedigrees was performed and the data was used for multipoint parametric linkage analyses. Following this scan, selected cases were analyzed by Affymetrix 6.0 SNP arrays in order to refine the contribution of copy number variations (CNVs) to the genetic basis of MDD.
We found a total of 18 genomic regions with nominal (LOD>1.3) linkage to MDD across the two isolates. Three genomic regions had genome-wide significant (LOD>3) linkages and were found at 2p13.2-p11.2, 14q31.12-q32.13 and 22q12.3. We also confirmed previous findings for MDD at 4q25, 11p15, 12q23-24, 13q31-32, 18q21-22 and 22q11-13. Six linkage regions were observed in both genetic isolates, while 12 other linkages demonstrated population-specific heterogeneity. We detected CNV rearrangements within 12 of the 18 linkage regions. Affected subjects had the highest rate of genomic instability within the linkage regions at 2p13.2-p11.2, 4q25-q28.2, 7p14.1, 8p23, 14q31.12-q32.13, 18q22.1 and 20p13.
The results obtained in this study suggest that mapping genes of complex diseases, including MDD, across genetically homogeneous isolates can help detect linkage signals and expedite the search for susceptibility genes when combined with methods that detect structural genomic variation in linkage regions.
本研究旨在运用分子和统计群体遗传学方法，确定高加索达吉斯坦土著民族遗传隔离群体中早发性重度抑郁症（MDD）的分子流行病学特征。
在我们名为“达吉斯坦遗传遗产，DGH”的长期研究项目中，确定了来自两个不同偏远高地隔离群体的两个多代系谱，这些群体中早发性MDD呈聚集性。第一个隔离群体包括48例MDD患者（19例在世），其中11例自杀；第二个隔离群体包括60例MDD患者（30例在世），其中12例自杀。通过一个包含地区精神病医院诊断结果的数据库以及我们自己基于俄罗斯翻译的、依据DSM-IV标准的DIGS软件进行的临床检查，确定了受影响家庭成员的表型。对系谱中的64名受影响和未受影响成员进行了10厘摩基因组扫描（Weber/CHLC 9.0 STRs），并将数据用于多点参数连锁分析。此次扫描之后，对选定病例进行了Affymetrix 6.0 SNP阵列分析，以细化拷贝数变异（CNV）对MDD遗传基础的贡献。
我们在两个隔离群体中总共发现了18个与MDD存在名义连锁（LOD>1.3）的基因组区域。三个基因组区域具有全基因组显著（LOD>3）连锁，分别位于2p13.2 - p11.2、14q31.12 - q32.13和22q12.3。我们还证实了先前在4q25、11p15、12q23 - 24、13q31 - 32、18q21 - 22和22q11 - 13发现的与MDD相关的结果。在两个遗传隔离群体中均观察到6个连锁区域，而其他12个连锁区域表现出群体特异性异质性。我们在18个连锁区域中的12个区域检测到CNV重排。在2p13.2 - p11.2、4q25 - q28.2、7p14.1、8p23、14q31.12 - q32.13、18q2
