J. Scott Stiffler

Genome-wide linkage survey for genetic loci that influence the development of depressive disorders in families with recurrent, early-onset, major depression

In this report, we describe the results of the first genome‐wide linkage survey for genetic loci that influence the development of unipolar Mood Disorders in 81 families identified by individuals with Recurrent, Early‐Onset, Major Depressive Disorder (RE‐MDD). Model‐free linkage analysis was performed using genotypes for 392 highly informative polymorphisms with an average spacing of 9 cM. The highest maximum LOD score observed, 8.19 (genome‐wide adjusted P ≪ 0.0001), occurred for Recurrent Major Depressive Disorder (R‐MDD) at D2S2321 (205 cM), located 121 kb proximal to CREB1. Nineteen chromosomal regions contained linkage peaks that reached genome‐wide statistical significance (genome‐wide adjusted P < 0.05) and ten of these were “highly significant” (adjusted P < 0.001). Six of the 19 linkage peaks were revealed only when the analysis included covariates to control for the effects of sex and linkage to CREB1. Sex‐specific susceptibility loci were common and preferentially affected the vulnerability of women to developing unipolar Mood Disorders. Five loci revealed evidence of interaction with the CREB1 locus in determining susceptibility (epistasis). A systematic candidate gene analysis is presented and potential overlaps of the linkage regions for unipolar Mood Disorders with those reported for other psychiatric disorders are discussed. The findings suggest that genes whose products participate in cellular signaling pathways that converge on CREB, as well as the target genes whose expression they regulate, may also harbor alleles that affect the development of Mood Disorders and related conditions.

Association of the APOE ε4 allele with clinical subtypes of late life depression

The APOE genotypes of 45 elderly inpatients with major depression were determined to investigate the relationship of this disorder to irreversible dementia in late life. We specifically tested the hypothesis that the frequency of the APOE e 4 allele is elevated in depressed elders with cognitive impairment or psychotic features, subtypes that have been reported to be at increased risk of developing Alzheimers disease (AD). The frequency of e 4 allele was not elevated in the overall group of 45 inpatients and, contrary to our expectation, was not associated with cognitive impairment in this group. In contrast, the e 4 allele frequency for the patients with psychotic features was nearly four times that for the patients without psychotic features and nearly double that of elderly controls. These data suggest that elderly depressed inpatients with cognitive impairment are at risk for developing AD by an e 4-independent pathway, while those with psychotic features are at risk for developing AD by an e 4-dependent pathway. These findings suggest that subtypes of idiopathic major depression in late life may serve as landmarks that distinguish separable pathogenetic pathways to AD.

Genome-wide linkage survey for genetic loci that affect the risk of suicide attempts in families with recurrent, early-onset, major depression

We previously described the results of a genome‐wide linkage survey for genetic loci that influenced the development of unipolar mood disorders in 81 families identified by individuals with Recurrent, Early‐Onset, Major Depressive Disorder (RE‐MDD) [Zubenko et al. 2003b; Am J Med Genet (Neuropsychiatr Genet) 123B:1–18]. In the current study, we extended this linkage analysis by including the history of a suicide attempt as a covariate to identify chromosomal regions that harbor genes that influence the risk of this behavior in the context of mood disorders. This approach identified six linkage peaks with maximum multipoint ΔLOD scores that reached genome‐wide adjusted levels of significance (2p, 5q, 6q, 8p, 11q, and Xq). Four of these (2p, 6q, 8p, and Xq) exceeded the criterion for “highly‐significant linkage” (genome‐wide adjusted P < 0.001) recommended by Lander and Kruglyak [1995; Nat Genet 11:241–246]. The strongest evidence for linkage was observed in analyses employing affected relative pairs (ARPs) with the most severe and disabling Mood Disorders: Depression Spectrum Disorder and RE‐MDD. The highest ΔLOD score that emerged from this linkage analysis, 5.08, occurred for ARPs with Depression Spectrum Disorder at D8S1145 (37.0 cM, 18.2 Mbps, P < 0.0001) at cytogenetic location 8p22‐p21. Significant linkage results on Xq arose from analyses of ARPs with RE‐MDD at DXS1047 (143 cM, 127.8 Mbps, ΔLOD = 3.87, P < 0.0001), a finding that may contribute to the higher rate of suicide attempts among women than men. These findings provide evidence for suicide risk loci that are independent of susceptibility loci for Mood Disorders, and suggest that the capacity for suicide risk loci to affect the development of suicidal behavior depends on the psychiatric disorder or subtype with which they interact.

Reductions in brain phosphatidylinositol kinase activities in alzheimer’s disease

BACKGROUND Converging lines of evidence suggest that alterations in the intracellular trafficking of the amyloid precursor protein, its derivatives, and other relevant proteins may contribute to the pathophysiology of Alzheimers disease (AD). Since phosphatidylinositol (PI) kinase plays a pivotal role in the sorting and transport of newly synthesized proteins to their final destinations, we explored the hypothesis that AD is associated with alterations in the specific activities of these enzymes in postmortem brain tissue. METHODS The specific activities of soluble and particulate pools of PI 3-kinase and PI 4-kinase from the frontal cortex were compared between 11 cases with histopathologically confirmed AD and 11 nondemented controls matched for sex, race, age at death, and postmortem interval. Potential associations of these activities with sociodemographic and clinical features were also explored. RESULTS AD was associated with 43-59% reductions in the specific activities of the soluble forms of both lipid kinases; but no significant change in the specific activities of the particulate species. Associations of these specific activities with sex, age at onset or death, duration of illness, postmortem interval, or densities of morphologic lesions in the frontal cortex were not observed among the 11 AD cases. CONCLUSIONS In addition to regulating protein sorting and trafficking, PI kinases participate in a wide range of cellular processes including protection from apoptosis, differentiation and cell growth, regulation of the cytoskeleton, and glucose metabolism. The results of this study suggest that one or more of these alterations in AD may result from a common abnormality in PI kinase regulation.

Clinically-Silent Mutation in the Putative Iron-Responsive Element in Exon 17 of the β-Amyloid Precursor Protein Gene

Three missense mutations in exon 17 of the /3-amyloid precursor protein (APP) gene have been reported to cosegregate in families with early onset Alzheimers disease (AD). All three mutations result in amino acid substitutions at codon 717 and may produce AD by altering the structure of the transmembrane domain of APP. Alternatively, the mutations may destabilize the stem of a putative iron-responsive element (IRE) in which they lie and confer pathogenicity by inactivating this negative regulatory element. We have detected a clinically-silent mutation in codon 716 that would also be expected to disrupt the putative IRE but results in no amino acid substitution. This result strongly suggests that the missense mutations at codon 717 produce AD by altering the amino acid sequence of APP rather than the IRE. Furthermore, the identification of a clinically-silent mutation among four point mutations that span only three nucleotides of exon 17 suggests that this region may be a mutational “hot” spot.

Clinical and neurobiological correlates of D10S1423 genotype in Alzheimer’s disease

BACKGROUND In a previous genome survey, we detected associations of alleles at six microsatellite loci with typical-onset AD, including the 234bp allele of the D10S1423 locus. The goal of the current study was to explore the clinical, neuropathological, and neurochemical correlates of the D10S1423 234bp allele in a group of 50 autopsy-confirmed cases of Alzheimers disease (AD) who lacked other brain diseases. METHODS Clinical assessments were performed as part of a longitudinal study of AD and related disorders. Autopsies were performed using standardized methods and diagnoses were made according to established criteria. Genotyping, morphometry, and neurochemical analyses were performed using postmortem brain tissue. RESULTS Patients with AD who carried the D10S1423 234bp allele manifested substantial reductions in dopamine levels in all six cortical regions examined. In contrast, carriers tended to have higher concentrations of cortical norepinephrine and revealed a dosage effect of the D10S1423 234bp allele. CONCLUSIONS These findings support the results of our genome survey and suggest that a novel susceptibility gene for AD resides near the D10S1423 locus. The characterization of biologically meaningful subtypes, including genotypic subtypes with particular neurobiological derangements, may be important for the advancement of experimental therapeutics in AD.