Verma Ranjana, Holmans Peter, Knowles James A, Grover Deepak, Evgrafov Oleg V, Crowe Raymond R, Scheftner William A, Weissman Myrna M, DePaulo J Raymond, Potash James B, Levinson Douglas F
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Biol Psychiatry. 2008 Jun 15;63(12):1185-9. doi: 10.1016/j.biopsych.2008.02.005. Epub 2008 Mar 25.
We reported genome-wide significant linkage on chromosome 15q25.3-26.2 to recurrent early-onset major depressive disorder (MDD-RE). Here we present initial linkage-disequilibrium (LD) fine mapping of this signal and sequence analysis of NTRK3 (neurotrophic receptor kinase-3), a biologically plausible candidate gene.
In 300 pedigrees informative for family-based association, 1195 individuals were genotyped for 795 single nucleotide polymorphism (SNPs). We resequenced 21 exons and 7 highly conserved NTRK3 regions in 176 MDD-RE cases to test for an excess of rare functional variants and, 176 controls for case-control analysis of common variants.
LD mapping showed nominally significant association in NTRK3, FLJ12484, RHCG, DKFZp547K1113, VPS33B, SV2B, SLCO3A1, RGMA, and MCTP2 with MDD-RE. In NTRK3, five SNPs had nominally significant p values (.035-.001). Sequence analysis revealed 35 variants (24 novel, including 9 rare exonic); the number of rare variants did not exceed chance expectation. Case-control analysis of 13 common variants showed modest nominal association of MDD-RE with rs4887379, rs6496463, and rs3825882 (p = .008, .048, and .034), which were in partial LD with four of five associated SNPs from the family-based experiment.
Common variants in NTRK3 or other genes identified might play a role in MDD-RE. However, much larger studies are required for full evaluation of this region.
我们报告了15号染色体q25.3 - 26.2区域与复发性早发性重度抑郁症（MDD - RE）存在全基因组显著连锁。在此，我们展示了该信号的初始连锁不平衡（LD）精细定位以及神经营养受体激酶3（NTRK3）的序列分析，NTRK3是一个生物学上合理的候选基因。
在300个适合基于家系关联分析的家系中，对1195名个体进行了795个单核苷酸多态性（SNP）的基因分型。我们对176例MDD - RE患者的21个外显子和7个高度保守的NTRK3区域进行了重测序，以检测罕见功能变异的过量情况，并对176名对照进行了常见变异的病例对照分析。
LD定位显示NTRK3、FLJ12484、RHCG、DKFZp547K1113、VPS33B、SV2B、SLCO3A1、RGMA和MCTP₂与MDD - RE存在名义上的显著关联。在NTRK3中，五个SNP具有名义上的显著p值（0.035 - 0.001）。序列分析揭示了35个变异（24个新变异，包括9个罕见外显子变异）；罕见变异的数量未超过预期概率。对13个常见变异的病例对照分析显示，MDD - RE与rs4887379、rs6496463和rs3825882存在适度的名义关联（p = 0.008、0.048和0.034），这三个变异与基于家系实验的五个关联SNP中的四个处于部分LD状态。
NTRK3或其他已鉴定基因中的常见变异可能在MDD - RE中起作用。然而，需要更大规模的研究来全面评估该区域。
