Zubenko George S, Hughes Hugh B, Stiffler J Scott, Zubenko Wendy N, Kaplan Barry B
Department of Psychiatry, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, USA.
Am J Med Genet. 2002 May 8;114(4):413-22. doi: 10.1002/ajmg.10381.
Recurrent (two or more episodes), early-onset (first episode at < or = 25 years) major depressive disorder (RE-MDD) is a strongly familial condition (lambda(first-degree relatives) = 8) whose malignant effects have a significant negative impact on the health and longevity of patients and their family members. The goal of this study was to identify candidate susceptibility loci that influence the development of RE-MDD. We completed a systematic survey of the human genome, conducted at an average resolution of 10 cM, for the identification of simple sequence tandem repeat polymorphisms (SSTRPs) that target susceptibility genes for RE-MDD by virtue of linkage disequilibrium. The efficiency of our association study was enhanced by genotyping pools of DNA from 100 adults with RE-MDD and 100 adult controls who had no personal or family history of mental disorders. Both groups included equal numbers of Caucasian men and women and were matched as closely as possible for age and ethnicity. Allelic associations with RE-MDD were observed for 19 of the 387 SSTRPs in the CHLC Human Screening Set/Weber Version 9. Sixteen of the 19 candidate susceptibility loci revealed significant allelic associations with RE-MDD in men (n = 7) or women (n = 9), but not in both sexes. Evidence for both risk and protective alleles was detected. Two of the candidate susceptibility loci reside within several Mb of loci previously reported-megabases to be linked to "comorbid alcoholism and depression" in families of individuals with alcoholism and to a broadly defined affected phenotype that included recurrent major depression in the families of patients with bipolar disorder. Although it has been suggested that the genes that influence risk for MDD in the two sexes may not be entirely the same, the results of our study suggest that sex specificity of susceptibility loci for RE-MDD may be the rule rather than the exception. The observed preponderance of sex-specific susceptibility loci for RE-MDD suggests that there may be important differences in the molecular pathophysiology of RE-MDD in men and women. Alternatively, our findings may reflect the existence of sex-specific differences in the molecular mechanisms that determine resilience to endogenous or environmental depressogenic stimuli.
复发性（两次或更多发作）早发性（首次发作年龄≤25岁）重度抑郁症（RE-MDD）是一种具有强烈家族聚集性的疾病（一级亲属的λ值 = 8），其恶性影响对患者及其家庭成员的健康和寿命有显著负面影响。本研究的目的是确定影响RE-MDD发病的候选易感基因座。我们以平均10厘摩的分辨率对人类基因组进行了系统调查，以鉴定通过连锁不平衡靶向RE-MDD易感基因的简单序列串联重复多态性（SSTRP）。通过对100名患有RE-MDD的成年人和100名无精神障碍个人或家族史的成年对照者的DNA样本池进行基因分型，提高了我们关联研究的效率。两组中白种男性和女性数量相等，并尽可能在年龄和种族上进行匹配。在CHLC人类筛选集/Weber第9版的387个SSTRP中，有19个观察到与RE-MDD的等位基因关联。19个候选易感基因座中的16个在男性（n = 7）或女性（n = 9）中显示出与RE-MDD显著的等位基因关联，但并非在两性中均有。检测到了风险等位基因和保护性等位基因的证据。其中两个候选易感基因座位于先前报道的与酗酒家庭中的“共病酒精中毒和抑郁症”以及双相情感障碍患者家庭中广泛定义的受影响表型（包括复发性重度抑郁症）连锁的基因座的几兆碱基范围内。尽管有人提出影响两性中MDD风险的基因可能并不完全相同，但我们的研究结果表明，RE-MDD易感基因座的性别特异性可能是规律而非例外。观察到的RE-MDD性别特异性易感基因座占优势表明，男性和女性RE-MDD的分子病理生理学可能存在重要差异。或者，我们的发现可能反映了在决定对内源性或环境性致抑郁刺激的恢复力的分子机制中存在性别特异性差异。
