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ABSTRACT: The brain-derived neurotrophic factor (BDNF) Val(66) Met allelic variation is linked to both the occurrence of mood disorders and antidepressant response. These findings are not universally observed, and the mechanism by which this variation results in increased risk for mood disorders is unclear. One possible explanation is an epistatic relationship with other neurotransmitter genes associated with depression risk, such as the serotonin-transporter-linked promotor region (5-HTTLPR). Further, it is unclear how the coexistence of the BDNF Met and 5-HTTLPR S variants affects the function of the affective and cognitive control systems. To address this question, we conducted a functional magnetic resonance imaging (fMRI) study in 38 older adults (20 healthy and 18 remitted from major depressive disorder). Subjects performed an emotional oddball task during the fMRI scan and provided blood samples for genotyping. Our analyses examined the relationship between genotypes and brain activation to sad distractors and attentional targets. We found that 5-HTTLPR S allele carriers exhibited stronger activation in the amygdala in response to sad distractors, whereas BDNF Met carriers exhibited increased activation to sad stimuli but decreased activation to attentional targets in the dorsolateral prefrontal and dorsomedial prefrontal cortices. In addition, subjects with both the S allele and Met allele genes exhibited increased activation to sad stimuli in the subgenual cingulate and posterior cingulate. Our results indicate that the Met allele alone or in combination with 5-HTTLPR S allele may increase reactivity to sad stimuli, which might represent a neural mechanism underlying increased depression vulnerability.
Genes Brain and Behavior 01/2012; 11(3):352-9. · 3.48 Impact Factor
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ABSTRACT: Although not observed in younger adult cohorts, in older individuals the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is associated with major depressive disorder (MDD) risk. It is further associated with subjective social support and magnetic resonance imaging (MRI) hyperintense lesions, clinical features independently related to MDD. We examined the relationship between this polymorphism and antidepressant remission rates in an elderly sample with MDD, while also testing for mediation effects of social support and hyperintensities. A total of 229 elderly Caucasian subjects with MDD completed baseline assessments, 1.5 T MRI, and BDNF genotyping. They received antidepressant medication under a structured treatment algorithm and were evaluated for remission at 3 and 6 months. At the 3-month evaluation, BDNF Val66Met genotype was not associated with remission (Wald's χ²=2.51, P=0.1131). When not controlling for multiple comparisons, Met66 allele carriers were more likely to be remitted at 6 months (χ²=4.32, P=0.0377) with an odds ratio of 1.82 (95% CI: 1.04, 3.22). This effect persisted after controlling for lesion volume and social support, neither of which mediated this relationship. Thus in this exploratory analysis, the Met66 allele may be associated with increased odds of remission in older subjects, but also with increased time to remission as there was no 3-month effect.
The Pharmacogenomics Journal 03/2010; 11(2):146-54. · 4.54 Impact Factor
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ABSTRACT: This longitudinal study examined the relationship between 2-year change in white matter hyperintense lesion (WML) volume and polymorphisms in genes coding for the angiotensin-II type 1 and type 2 receptors, AGTR1 A1166C and AGTR2 C3123A, respectively. 137 depressed and 94 non-depressed participants aged >or=60 years were enrolled. Standard clinical evaluations were performed on all participants and blood samples obtained for genotyping. 1.5-T MRI (magnetic resonance imaging) data were obtained at baseline and approximately 2 years later. These scans were processed using a semi-automated segmentation process, which allowed for the calculation of WML volume at each time point. Statistical models were tested for the relationship between change in WML volume and genotype, while also controlling for age, sex, diagnostic strata, baseline WML volume and comorbid cerebrovascular risk factors. In men, AGTR1 1166A allele homozygotes exhibited significantly less change in WML volume than 1166C carriers. We also found that men reporting hypertension (HTN) with the AGTR2 3123C allele exhibit less change in WML volume than hypertensive men with the 3123A allele, or men without HTN. There were no significant relationships between these polymorphisms and change in WML volume in women. No significant gene-gene or gene-depression interactions were observed. Our results parallel earlier observed gender differences of the relationship between other renin-angiotensin system polymorphisms and HTN. Further work is needed to determine whether these observed relationships are secondary to polymorphisms affecting response to antihypertensive medication, and whether antihypertensive medications can slow WML progression and lower the risk of morbidity associated with WMLs.
Molecular psychiatry 03/2009; 15(8):816-22. · 15.05 Impact Factor
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Molecular Psychiatry 11/2006; 11(10):887-9. · 13.67 Impact Factor
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Journal of Medical Genetics 10/2003; 40(9):e106. · 6.36 Impact Factor
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A Ashley-Koch,
E R Bonner,
P C Gaskell,
S G West,
R Tim,
C M Wolpert,
R Jones,
C D Farrell,
M Nance,
I K Svenson,
D A Marchuk,
R M Boustany,
J M Vance,
W K Scott,
M A Pericak-Vance
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ABSTRACT: We evaluated seven families segregating pure, autosomal dominant familial spastic paraplegia (SPG) for linkage to four recently identified SPG loci on chromosomes 2q (1), 8q (2), 12q (3), and 19q (4). These families were previously shown to be unlinked to SPG loci on chromosomes 2p, 14q, and 15q. Two families demonstrated linkage to the new loci. One family (family 3) showed significant evidence for linkage to chromosome 12q, peaking at D12S1691 (maximum lod = 3.22). Haplotype analysis of family 3 did not identify any recombinants among affected individuals in the 12q candidate region. Family 5 yielded a peak lod score of 2.02 at marker D19S868 and excluded linkage to other known SPG loci. Haplotype analysis of family 5 revealed several cross-overs in affected individuals, thereby potentially narrowing the SPG12 candidate region to a 5-cM region between markers D19S868 and D19S220. Three of the families definitively excluded all four loci examined, providing evidence for further genetic heterogeneity of pure, autosomal dominant SPG. In conclusion, these data confirm the presence of SPG10 (chromosome 12), potentially reduce the minimum candidate region for SPG12 (chromosome 19q), and suggest there is at least one additional autosomal dominant SPG locus.
Neurogenetics 04/2001; 3(2):91-7. · 3.35 Impact Factor
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A Ashley-Koch,
C M Wolpert,
M M Menold,
L Zaeem,
S Basu,
S L Donnelly,
S A Ravan,
C M Powell,
M B Qumsiyeh,
A S Aylsworth,
J M Vance,
J R Gilbert,
H H Wright,
R K Abramson,
G R DeLong,
M L Cuccaro,
M A Pericak-Vance
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ABSTRACT: Genome-wide scans have suggested that a locus on 7q is involved in the etiology of autistic disorder (AD). We have identified an AD family in which three sibs inherited from their mother a paracentric inversion in the chromosome 7 candidate region (inv(7)(q22-q31.2)). Clinically, the two male sibs have AD, while the female sib has expressive language disorder. The mother carries the inversion, but does not express AD. Haplotype data on the family suggest that the chromosomal origin of the inversion was from the children's maternal grandfather. Based on these data, we have genotyped 76 multiplex (>/=2 AD affecteds/family) families for markers in this region of 7q. Two-point linkage analysis yielded a maximum heterogeneity lod score of 1.47 and maximum lod score (MLS) of 1.03 at D7S495. Multipoint MLS and NPL analyses resulted in peak scores of 1.77 at D7S2527 and 2.01 at D7S640. Examination of affected sibpairs revealed significant paternal (P = 0.007), but not maternal (P = 0. 75), identity-by-descent sharing at D7S640. Significant linkage disequilibrium was detected with paternal (P = 0.02), but not maternal (P = 0.15), transmissions at D7S1824 in multiplex and singleton families. There was also evidence for an increase in recombination in the region (D7S1817 to D7S1824) in the AD families versus non-AD families (P = 0.03, sex-averaged; and P = 0.01, sex-specific). These results provide further evidence for the presence of an AD locus on chromosome 7q, as well as provide evidence suggesting that this locus may be paternally expressed.
Genomics 11/1999; 61(3):227-36. · 3.02 Impact Factor
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ABSTRACT: We performed genome-wide model dependent and independent analyses on a simulated data set of 400 families segregating for a rare disorder. Regions on chromosomes 1, 3, and 5 were consistently indicated across the various analyses performed. Follow-up analyses included stratification for locus heterogeneity and clinical phenotype and studies of gene x gene and gene x environment interaction. The region around D1G024 was most notable, showing strong association and linkage with the trait. We also identified regions D3G043-46 and D5G037-39 by strong linkage and association findings and region D1G001-09 by linkage analysis. A complex statistical interaction was suggested between D1G024, D3G046 and environmental factor 1. This report suggests that traditional methods of analysis can be implemented to analyze and describe the mechanisms that may underlie the more complex genetic disorders.
Genetic Epidemiology 02/1999; 17 Suppl 1:S473-8. · 3.44 Impact Factor
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A. Ashley-Koch,
C.M. Wolpert,
M.M. Menold,
L. Zaeem,
S. Basu,
S.L. Donnelly,
S.A. Ravan,
C.M. Powell,
M.B. Qumsiyeh,
A.S. Aylsworth,
J.M. Vance,
J.R. Gilbert,
H.H. Wright,
R.K. Abramson,
G.R. DeLong,
M.L. Cuccaro,
M.A. Pericak-Vance
[show abstract]
[hide abstract]
ABSTRACT: Genome-wide scans have suggested that a locus on 7q is involved in the etiology of autistic disorder (AD). We have identified an AD family in which three sibs inherited from their mother a paracentric inversion in the chromosome 7 candidate region (inv(7)(q22–q31.2)). Clinically, the two male sibs have AD, while the female sib has expressive language disorder. The mother carries the inversion, but does not express AD. Haplotype data on the family suggest that the chromosomal origin of the inversion was from the children's maternal grandfather. Based on these data, we have genotyped 76 multiplex (≥2 AD affecteds/family) families for markers in this region of 7q. Two-point linkage analysis yielded a maximum heterogeneity lod score of 1.47 and maximum lod score (MLS) of 1.03 at D7S495. Multipoint MLS and NPL analyses resulted in peak scores of 1.77 at D7S2527 and 2.01 at D7S640. Examination of affected sibpairs revealed significant paternal (P = 0.007), but not maternal (P = 0.75), identity-by-descent sharing at D7S640. Significant linkage disequilibrium was detected with paternal (P = 0.02), but not maternal (P = 0.15), transmissions at D7S1824 in multiplex and singleton families. There was also evidence for an increase in recombination in the region (D7S1817 to D7S1824) in the AD families versus non-AD families (P = 0.03, sex-averaged; and P = 0.01, sex-specific). These results provide further evidence for the presence of an AD locus on chromosome 7q, as well as provide evidence suggesting that this locus may be paternally expressed.
Genomics.
