D2S2944 identifies a likely susceptibility locus for recurrent, early-onset, major depression in women

Abstract

Recurrent, early-onset, major depressive disorder (RE-MDD) is a strongly familial condition whose malignant effects have a significant negative impact on the health and longevity of patients and their family members. Sixteen of the 19 candidate susceptibility loci identified by a recent genome survey revealed allelic associations with RE-MDD in men or women, but not in both sexes. The association of D2S2944 alleles and genotypes with RE-MDD and related disorders was evaluated using a case-control study design employing 100 adults with RE-MDD and 100 adult controls who had no personal or family history of mental disorders. The results of the case-control study were subsequently evaluated in a sample of 81 families ascertained through probands with RE-MDD using the transmission/disequilibrium test. The frequency of the D2S2944 124-bp allele among women with RE-MDD was approximately three times that for female controls (P = 0.0003). Women who carried the D2S2944 124-bp allele revealed a significantly elevated risk of developing RE-MDD, as indicated by an odds ratio of 4.5 compared to female controls (PϽ0.001). In contrast, men with RE-MDD did not have an increased frequency of this allele compared to male controls, and men who were carriers did not exhibit an increased risk of developing RE-MDD or related disorders. Our findings also suggest that the D2S2944 124-bp allele increases the risk of alcohol and other substance use disorders among women with RE-MDD. The transmission/disequilibrium test provided confirmatory evidence of these sex-specific findings within families. The results of this study confirm the existence of sex-specific susceptibility loci for RE-MDD, and suggest 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. The identification and characterization of the D2S2944 susceptibility locus for RE-MDD and related substance use disorders is likely to provide important new insights into the clinical biology, treatment, and prevention of these disorders.

Linkage scan for quantitative traits identifies new regions of interest for substance dependence in the Collaborative Study on the Genetics of Alcoholism (COGA) sample

“…Work by Zubenko and colleagues has also suggested a role of CREB1 on mood disorders; this lies 20 cM centromeric to our linkage peak (Zubenko et al, 2003a). These authors have also identified a sex-specific association between the 124bp repeat allele of D2S944 and recurrent, early-onset major depression and with anxious depression in an independent U.S. and Dutch sample (Beem et al, 2006;Philibert et al, 2003;Zubenko et al, 2002). Due to the high level of comorbidity between alcohol and drug dependence and major depression, and as indexed by a high LOD score of 3.49 for comorbid alcoholism and major depression in prior linkage analyses using COGA data (Nurnberger, Jr. et al, 2001), this region on chromosome 2 may be tapping into a region of susceptibility for both disorders.…”

Combined Linkage and Association Analyses of the 124-bp Allele of Marker D2S2944 with Anxiety, Depression, Neuroticism and Major Depression

“…Hence, its reported effects on recurrent early-onset MDD in females (Zubenko et al, 2002b) do not seem to generalize to these quantitative risk factors.…”

“…Those effects occur in the absence of evidence for linkage, although the association cannot be spurious due to stratification effects because the association is partitioned in between and within family contributions. Zubenko et al (2002b) reported association for recurrent early-onset MDD in females only. Although we did not find any association for females, some evidence for linkage in this region was found for anxious depression as judged by the estimates of the variances.…”

“…In a subsequent study, Zubenko et al (2002b) presented a more detailed comparison of the frequencies of each allele of D2S2944 in the same sample of cases and controls. For females, the D2S2944 124-bp allele was significantly more common in cases than controls (odds ratio 4.5, 95% CI 1.9-10.8).…”

Risk for recurrence in depression

“…That is, individuals with more than one episode of depression may also have earlier ages at onset, more severe episodes, more comorbid disorders, and a stronger family history of psychopathology. It is also conceivable that all of these clinical picture variables reflect an underlying genetic vulnerability to the recurrent type of depression, particularly given the likely genetic transmission of recurrent depression (Kendler et al, 1992;Sullivan et al, 2000;Zubenko et al, 2002). Earlier age at onset, more severe early episodes of depression, greater comorbidity, and greater family history of psychopathology may all reflect an underlying genetic predisposition to the more severe recurrent type of depression.…”