D10S1423 identifies a susceptibility locus for Alzheimer's disease in a prospective, longitudinal, double-blind study of asymptomatic individuals

Zubenko, George S.; Hughes, Hugh B.; Stiffler, J. Scott

doi:10.1038/sj.mp.4000900

Cited by 31 publications

(26 citation statements)

References 61 publications

(51 reference statements)

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“…The effect of a second susceptibility gene (in this case, the MAOA gene) may become apparent, however, when gene-gene interactions with other genes are analysed. 24,25 We have illustrated the effectiveness of this approach in our gene-gene interaction analysis, and have also shown how the relationship of the associated susceptibility loci (in this case the MAOA-uVNTR and NETpPR) may be easily characterised in a contingency table.…”

Section: Discussionmentioning

confidence: 99%

Gene-gene interaction between the monoamine oxidase A gene and solute carrier family 6 (neurotransmitter transporter, noradrenalin) member 2 gene in anorexia nervosa (restrictive subtype)

et al. 2003

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We earlier found an association between anorexia nervosa (AN) restrictive subtype (AN-R) and an inserted sequence within the NETpPR, a polymorphic region located in the promoter of the solute carrier family 6 (neurotransmitter transporter, noradrenalin) member 2 (SLC6A2) gene. To further examine the noradrenergic system in AN-R we performed an association study with a functional polymorphism (MAOAuVNTR) in the promoter of the monoamine oxidase A (MAOA) gene. Since monoamine oxidase A metabolises noradrenalin, a positive association with the MAOA gene would be biologically plausible. The transmission disequilibrium test and 95 trios/duos (AN-R females þ biological parents) showed the main effect of the longer, more transcriptionally active form of the MAOA-uVNTR (MAOA-L) to be statistically non-significant (McNemar's v 2 ¼ 1.4, df ¼ 1, P ¼ 0.238, odds ratio: 1.4, 95% CI 0.8 -2.7). A case-control approach supported this finding. We then stratified the MAOA-uVNTR TDT data according to the (a) NETpPR genotype of the AN-R females, and (b) NETpPR allele transmitted from NETpPR-S4/L4 heterozygous mothers. In both cases, contingency table analysis revealed previously unreported genegene interaction between the MAOA and SLC6A2 genes (P ¼ 0.019 and 0.019, respectively). Receiving an MAOA-L allele more than doubles the risk for developing AN-R, conditional on an individual also being a NETpPR-L4 homozygote (stratum-specific odds ratio: 2.4, 95% CI 1.1-6.0). These results suggest important involvement of the noradrenergic system in the biological underpinnings of AN-R.

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Section: Discussionmentioning

confidence: 99%

Gene-gene interaction between the monoamine oxidase A gene and solute carrier family 6 (neurotransmitter transporter, noradrenalin) member 2 gene in anorexia nervosa (restrictive subtype)

et al. 2003

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“…33 The efficiency of this 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. This case-control strategy for identifying genetic determinants that contribute to the expression of complex, non-Mendelian human disorders, which we have also previously employed to identify susceptibility loci for Alzheimer's disease, [34][35][36][37][38][39][40] is receiving growing support in the human genetics community. 41 In our previous investigation, allelic associations with RE-MDD were observed for 19 of the 387 SSTRPs employed in the analysis.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2002

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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.

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“…10 Furthermore, the experiment-wide significance levels in at least two of the positive studies were only marginal, 1,3 and the association was only evident when controlling for the presence of APOE e4 in the third study. 2 Finally, the fourth analysis, with the greatest number of cases, failed to replicate these findings altogether. 4 Of note, several research groups using varying samples and various methods of linkage and/or association analysis [5][6][7][8]11 have implicated chromosome 10 as harboring a novel AD locus.…”

mentioning

confidence: 72%

“…SIR -Recently, three studies reported genetic association of an anonymous microsatellite marker on chromosome 10p12 (D10S1423) and Alzheimer's disease (AD), [1][2][3] whereas a fourth study failed to replicate these findings 4 . At least four linkage studies have implicated regions on chromosome 10 as likely to harbor an AD susceptibility gene [5][6][7][8] ; however, all reported linkage peaks map considerably distal to D10S1423 (440 cM).…”

mentioning

confidence: 82%

No association between marker D10S1423 and Alzheimer's disease

et al. 2003

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D10S1423 identifies a susceptibility locus for Alzheimer's disease in a prospective, longitudinal, double-blind study of asymptomatic individuals

Cited by 31 publications

References 61 publications

Gene-gene interaction between the monoamine oxidase A gene and solute carrier family 6 (neurotransmitter transporter, noradrenalin) member 2 gene in anorexia nervosa (restrictive subtype)

Gene-gene interaction between the monoamine oxidase A gene and solute carrier family 6 (neurotransmitter transporter, noradrenalin) member 2 gene in anorexia nervosa (restrictive subtype)

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

No association between marker D10S1423 and Alzheimer's disease

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