D10S1423 identifies a susceptibility locus for Alzheimer's disease (AD7) in a prospective, longitudinal, double-blind study of asymptomatic individuals: results at 14 years.

Typical forms of Alzheimer's disease (AD) appear to be influenced by multiple susceptibility loci. This report describes the prospective, longitudinal, double-blind assessment of the age-specific risk of AD encountered by 325 asymptomatic first-degree relatives of AD probands who carried the D10S1423 (AD7) 234 bp allele, the APOE E4 allele, or both, after 14 years of systematic follow-up. A total of 30 incident cases of AD were detected during the first 3752 subject-years of surveillance. The effects of carrying either or both of the D10S1423 234 bp and APOE E4 alleles on the age-specific risk of developing AD were determined using Kaplan-Meier survival analysis. The risk of developing AD was the greatest for individuals who carried both alleles (Mantel-Cox statistic = 16.46, df = 3, P = 0.0009; Breslow statistic = 13.38, df = 3, P = 0.004). Cox proportional hazards models were developed to estimate the risk ratios for each genotype, controlling for the potential effects of age at recruitment, sex, and years of education. Only individuals who carried both risk alleles exhibited a risk ratio that differed significantly from 1 (risk ratio = 7.5, P = 0.002, 95% CI = 2.1-27.0). Neither age at recruitment, sex, nor years of education made significant contributions to the model, although women tended to be at greater risk (P = 0.06). Recent evidence that D10S1423 resides within open reading frame C10orf112, whose predicted product resembles a low-density lipoprotein receptor, suggests a molecular mechanism for this gene-gene interaction.

Genetic linkage of region containing the CREB1 gene to depressive disorders in families with recurrent, early-onset, major depression: a re-analysis and confirmation of sex-specific effect.

A previously published model-free linkage analysis of chromosome 2q33-35, highlighted by previous case-control studies and supported by within-family analyses employing the transmission disequilibrium test, revealed evidence of sex-specific linkage of the CREB1-containing region of 2q to unipolar mood disorders among women in 81 recurrent, early-onset, major depressive disorder (RE-MDD) families. Since it has been reported that the LODPAL program from S.A.G.E. v.4.0 used to conduct this previous linkage analysis suffers from an increased type I error rate that is exacerbated by covariates such as sex, we re-analyzed the evidence for this sex-specific linkage result using a simulation approach to estimate the empirical significance of our previous results. The results continue to support sex-specific linkage of the CREB1 region to mood disorders among women from families with RE-MDD. Moreover, these results have been supported by a host of additional published findings that implicate sequence variations in CREB1 in the sex-dependent development of syndromic mood disorders, as well as related clinical features and disorders.

Genetics of recurrent early-onset major depression (GenRED): final genome scan report.

OBJECTIVE: The authors carried out a genomewide linkage scan to identify chromosomal regions likely to contain genes that contribute to susceptibility to recurrent early-onset major depressive disorder, the form of the disorder with the greatest reported risk to relatives of index cases. METHOD: Microsatellite DNA markers were studied in 656 families with two or more such cases (onset before age 31 in probands and age 41 in other relatives), including 1,494 informative "all possible" affected relative pairs (there were 894 independent affected sibling pairs). Analyses included a primary multipoint allele-sharing analysis (with ALLEGRO) and a secondary logistic regression analysis taking the sex of each relative pair into account (male-male, male-female, female-female). RESULTS: Genomewide suggestive evidence for linkage was observed on chromosome 15q25-q26 (at 105.4 centimorgans [cM]). The authors previously reported genomewide significant linkage in this region in the first 297 families. In the secondary analysis, after empirical genomewide correction for multiple testing, suggestive linkage results were observed on chromosome 17p12 (28.0 cM, excess sharing in male-male and male-female pairs) and on chromosome 8p22-p21.3 (25.1 cM, excess sharing in male-male pairs). CONCLUSIONS: These regions of chromosomes 15q, 17p, and 8p might contain genes that contribute to susceptibility to major depression and related disorders. Evidence for linkage has been reported independently in the same regions of chromosome 15q for major depression and of chromosome 8p for related personality traits.

Reduced age-related cataracts among elderly persons who reach age 90 with preserved cognition: a biomarker of successful aging?

Tissue damage due to oxidative stress has been implicated in aging, memory loss, and cataract formation. We hypothesized that persons who achieved exceptional longevity with preserved cognition (successful aging [SAG]) would exhibit a lower rate of age-related cataract (ARC) than the general population. The age-specific rates of ARC for a group of 100 (50 male, 50 female) elderly persons who reached at least age 90 years with preserved cognition were compared to the corresponding rates of ARC reported in five population-based studies. The principal finding of this report was that the SAG group manifested a significant reduction in the age-specific rate and lifetime cumulative incidence of ARC compared to the general population. Steroid use, alcohol consumption, gout, and skin lesions resulting from excessive sun exposure emerged as risk factors. Our findings suggest that the progressive development of lens opacities may be reflective of degenerative events occurring more generally throughout the body.

A collaborative study of the emergence and clinical features of the major depressive syndrome of Alzheimer's disease.

OBJECTIVE: This report provides a description of the prevalence and clinical features of the major depressive syndrome of Alzheimer's disease using data derived from structured diagnostic assessments of 243 patients with probable Alzheimer's disease and 151 nondemented elderly comparison subjects. METHOD: Subjects were characterized by a consortium of four Alzheimer's disease research centers and the Geriatric Psychiatry Branch of the National Institute of Mental Health. All sites administered the Clinical Assessment of Depression in Dementia, a structured, anchored diagnostic interview that was developed to reliably diagnose and characterize major depressive episodes in this population. RESULTS: Despite the use of a common, reliable methodology for the assessment and diagnosis of major depressive episodes, the prevalence of major depression in Alzheimer's disease ranged widely from 22.5% to 54.4% across the recruitment sites. The prevalence of major depressive episodes among Alzheimer's disease patients in the aggregate sample exceeded that for elderly comparison subjects and reached nearly 50% among the most severely demented patients. Alzheimer's disease patients with a current major depressive episode had earlier mean ages at onset, a higher mean Hamilton Depression Rating Scale score, and were more likely to be experiencing psychotic symptoms than those who had not developed a major depressive episode. Although the major depressive episodes of Alzheimer's disease patients and nondemented elderly comparison subjects included similar numbers of depressive symptoms, patients with Alzheimer's disease were more likely to report a diminished ability to concentrate or indecisiveness and less likely to experience sleep disturbances and feelings of worthlessness or excessive guilt during their major depressive episodes. None of the clinical features of major depression differed significantly in frequency among depressed Alzheimer's disease patients with mild, moderate, or severe dementia. Concurrent psychotic symptoms progressively increased with dementia severity. CONCLUSIONS: The high rate of major depressive episodes that occur after the onset of cognitive impairment among patients with Alzheimer's disease (the majority of whom had no premorbid history of major depression), common emergence in the early stages of dementia when symptoms of cognitive impairment are least likely to contribute to the syndromal diagnosis of major depression, and differences in the clinical presentations of the major depressive episodes of Alzheimer's disease patients and nondemented elderly comparison subjects, all support the validity of the major depressive syndrome of Alzheimer's disease. Our findings suggest that the major depressive syndrome of Alzheimer's disease may be among the most common mood disorders of older adults.

Genome survey for susceptibility loci for recurrent, early-onset major depression: results at 10cM resolution.

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.

Genetic segregation analysis of recurrent, early-onset major depression: evidence for single major locus transmission.

Coordinated efforts are now underway to identify susceptibility genes for unipolar major depressive disorder (MDD) and related disorders. These studies have focused on recurrent, early-onset MDD (RE-MDD), thought to be the most familial form of this disorder. The goal of this study was to conduct a complex segregation analysis of recurrent MDD and other major mood disorders aggregating in families identified by probands with RE-MDD. Eighty-one families were identified through probands over the age of 18 who met criteria for recurrent (> or =2 episodes), early-onset (< or =25 years), nonpsychotic, unipolar MDD (RE-MDD) and included 407 first-degree relatives and 835 extended relatives. Psychiatric diagnoses for probands and their family members who provided blood samples were formulated from structured personal interviews, structured family history assessments, and available medical records. The remaining family members who participated and those who were deceased were evaluated through the family history method augmented by available medical records. Best-estimate diagnoses were made during a consensus conference according to established diagnostic criteria. Segregation analyses were performed using the REGD routine in S.A.G.E. release 4.0. The segregation analysis of recurrent MDD supported a sex-independent Mendelian codominant model. Analysis of major mood disorders supported a sex-independent Mendelian dominant model. Interestingly, inclusion of spousal residual correlations provided better fitting models for recurrent MDD but not the broader phenotype of major mood disorders. Unlike unipolar MDD, the lifetime prevalence of bipolar I disorder in this sample of families did not exceed the reported population prevalence [Zubenko et al., 2001]. Our results suggest that a major locus contributes to the expression of recurrent MDD and possibly other major mood disorders within families identified by probands with RE-MDD. Due to the limitations of the segregation analysis model, our results cannot address whether the same major locus is segregating across families in our sample or whether multiple major loci are involved (genetic heterogeneity). The absence of aggregation of bipolar I disorder in these families strongly suggests that while the genetic determinants of unipolar and bipolar disorders may overlap, they are not identical. Our findings illustrate the advantage of employing families identified by probands with RE-MDD in studies designed to detect susceptibility loci for unipolar MDD and related disorders.

Genetic linkage of region containing the CREB1 gene to depressive disorders in women from families with recurrent, early-onset, major depression.

This report describes the results of a model-free linkage analysis of six polymorphic markers, located in a 15 cM region of chromosome 2q33-35, and unipolar Mood Disorders in 81 families identified by probands with Recurrent, Early-Onset Major Depressive Disorder (RE-MDD), a severe and familial form of clinical depression. Our findings reveal significant evidence of linkage of unipolar Mood Disorders to a 451 Kb region of 2q33-34 flanked by D2S2321 and D2S2208 in these families. Increasing peak LOD scores were observed in both the single point and multipoint analyses for Mood Disorder phenotypes whose definitions embodied progressively less stringent severity criteria for inclusion in the affected group. The sex-dependent multipoint linkage analysis of any Major or Minor Mood Disorders produced LOD scores that reached 6.331 and 6.866 at D2S2321 and D2S2208, respectively. Linkage of Mood Disorders to this region was observed exclusively among female affected relative pairs; no suggestion of linkage was observed when male affected relative pairs were analyzed. These observations imply that a sex-specific susceptibility gene in this region contributes to the vulnerability of women in these families to the development of unipolar Mood Disorders that ranged in severity from minor to severe at the time of clinical assessment. The region between the markers that yielded the peak LOD score includes the CREB1 gene, which encodes a cAMP-responsive element-binding protein (CREB) that is a member of the bZIP family of transcription factors. Based on considerable clinical and preclinical evidence, CREB1 is an attractive candidate for a susceptibility gene for unipolar Mood Disorders. The sex-specificity of the susceptibility locus identified by our study may result from reported synergistic interactions of CREB with nuclear estrogen receptors.

Genome survey for loci that influence successful aging: results at 10-cM resolution.

OBJECTIVE: A systematic genome survey was initiated to identify loci that affect the likelihood of reaching age 90 with preserved cognition (successful aging). METHODS: The genome survey was conducted at 10-cM resolution for simple sequence tandem repeat polymorphisms (SSTRPs) that identify genes for Successful AGing (SAG loci) by virtue of linkage disequilibrium. Efficiency was enhanced by genotyping pools of DNA from 100 cognitively intact elders and 100 young (18-25 years) adults. The comparison groups included equal numbers of white men and women of similar ethnicity that were recruited from the southwestern Pennsylvania region. RESULTS: Our genome survey identified nine SAG candidate loci that may influence the likelihood of reaching age 90 or more with preserved cognition. Two of the autosomal SAG loci revealed stronger allelic associations with successful aging in men than women (D1S1728, D8S264) and two were located on sex chromosomes (DXS9902, DYS390). DXS9902 resides within a predicted gene, whereas six of the SAG loci are located within regions previously reported to show linkage to other phenotypes. CONCLUSIONS: The results of our study suggest that loci with differential effects on the successful aging of men and women may be common. The majority of the SAG candidate loci detected in this study overlap with regions previously reported to show linkage to susceptibility genes for cardiovascular disorders, psychiatric disorders, and the accumulation of tissue damage resulting from oxidative stress.

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 DeltaLOD 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 DeltaLOD 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, DeltaLOD = 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.

Genetic segregation analysis of alcohol and other substance-use disorders in families with recurrent, early-onset major depression.

OBJECTIVE: The goal of this study was to conduct a complex segregation analysis of alcohol and other substance-use disorders in families identified by probands with recurrent, early-onset major depression (RE-MDD). METHOD: Eighty-one families were identified through probands over the age of 18, who met criteria for recurrent (> or = 2 episodes), early-onset (< or = 25 years), nonpsychotic, unipolar major depression (RE-MDD) and included 407 first-degree relatives and 835 extended relatives. Psychiatric diagnoses for probands and their family members who provided blood samples were formulated from structured personal interviews, structured family history assessments, and available medical records. The remaining family members who participated and those who were deceased were evaluated through the family history method augmented by available medical records. Best estimate diagnoses were made during a consensus conference according to established diagnostic criteria. Segregation analyses were performed using the REGD routine in S.A.G.E. release 4.0. RESULTS: The best-fitting models for the transmission of "alcohol use disorders" or "alcohol/other substance use disorders" were sex-dependent Mendelian recessive models with significant residual spousal effects. Moreover, the parameter estimates for the models were very similar for these phenotypes. In contrast, the segregation analysis of "substance use disorder" supported a transmissible, but non-Mendelian, major effect. CONCLUSIONS: Our results suggest that a major locus contributes to the expression of alcohol use disorders or alcohol/other substance-use disorders within families identified by probands with RE-MDD. Due to the limitations of the segregation analysis model, our results cannot address whether the same major locus is segregating across families in our sample or whether multiple major loci are involved (genetic heterogeneity). Previous studies supported single gene transmission of recurrent major depression and major mood disorders in these families [Marazita et al. Am. J. Hum. Genet. 1997, 61, 1370-1378; Maher et al. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 2002. 114 (2), 214-221]. Mounting evidence suggests that at.least some of this "comorbidity" may result from the effects of shared susceptibility genes or an overlap in the sets of genes that contribute to the vulnerability of developing these mental disorders [Zubenko, G.S. Mol. Psychiatry 2000, 5, 131-136].

Genome survey for loci that influence successful aging: sample characterization, method validation, and initial results for the Y chromosome.

OBJECTIVE: A systematic genome survey was initiated to identify loci that affect the likelihood of reaching age 90 with preserved cognition. This communication describes the clinical characterization and comparison of the experimental groups, validation of the experimental method, and results for the Y chromosome. METHODS: The genome survey was conducted at 10 cM resolution for simple sequence tandem repeat polymorphisms (SSTRPs) that identify genes for successful aging by virtue of linkage disequilibrium. Efficiency was enhanced by genotyping pools of DNA from 100 cognitively intact elders (50 men/50 women) and 100 young (age 18-25 years) adults matched for sex, race, ethnicity, and geographic location. RESULTS: Elders (94 nonagenarians, 6 centenarians) manifested preserved cognition, as reflected by clinical and psychometric assessments; "good" average capacity to carry out their activities of daily living; and the majority were living independently despite multiple medical conditions. None had a history of mental disorders in early or middle adulthood, only one was a current smoker, and 80% consumed alcohol less than once each month. The genome survey method detected the expected elevation of the APOE epsilon2 allele frequency, and reciprocal reduction in the epsilon4 frequency, among the elders, compared with the young adults. It also detected significant differences in the allelic distributions of DYS389 and DYS390, which are separated by only 2.6 Mb near the centromere of Yq. CONCLUSIONS: These results suggest that several behavioral and genetic factors may contribute to the likelihood of achieving exceptional longevity with preserved cognition.

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.

Genomewide significant linkage to recurrent, early-onset major depressive disorder on chromosome 15q.

A genome scan was performed on the first phase sample of the Genetics of Recurrent Early-Onset Depression (GenRED) project. The sample consisted of 297 informative families containing 415 independent affected sibling pairs (ASPs), or, counting all possible pairs, 685 informative affected relative pairs (555 ASPs and 130 other pair types). Affected cases had recurrent major depressive disorder (MDD) with onset before age 31 years for probands or age 41 years for other affected relatives; the mean age at onset was 18.5 years, and the mean number of depressive episodes was 7.3. The Center for Inherited Disease Research genotyped 389 microsatellite markers (mean spacing of 9.3 cM). The primary linkage analysis considered allele sharing in all possible affected relative pairs with the use of the Z(lr) statistic computed by the ALLEGRO program. A secondary logistic regression analysis considered the effect of the sex of the pair as a covariate. Genomewide significant linkage was observed on chromosome 15q25.3-26.2 (Zlr=4.14, equivalent LOD = 3.73, empirical genomewide P=.023). The linkage was not sex specific. No other suggestive or significant results were observed in the primary analysis. The secondary analysis produced three regions of suggestive linkage, but these results should be interpreted cautiously because they depended primarily on the small subsample of 42 male-male pairs. Chromosome 15q25.3-26.2 deserves further study as a candidate region for susceptibility to MDD.

Genetics of recurrent early-onset depression (GenRED): design and preliminary clinical characteristics of a repository sample for genetic linkage studies.

This is an initial report on a six-site collaborative project, Genetics of Recurrent Early-Onset Depression (GenRED). This is a study of a large sample of families with recurrent major depressive disorder (DSM-IV) beginning by the age 30 in probands or 40 in relatives. Evidence suggests that early onset and recurrence of depressive episodes predict substantially increased risk of depression in first-degree relatives compared with the general population, suggesting that susceptibility genes might be mapped with this phenotype. The projected sample of 800-1,000 affected sibling pairs (ASPs) and other relatives will be studied using genome scan methods. Biological materials and blinded clinical data will be made available through the NIMH cell repository program. The sample should have good-to-excellent power to detect a locus associated with a 24% or greater population-wide increase in risk to siblings. We describe 838 affected individuals from the first 305 families containing 434 independent ASPs, or 613 ASPs counting all possible pairs. The mean age at the onset was 18.5 years, with a mean of 7.3 episodes and longest episode of 655 days. Almost all subjects had experienced at least 4 weeks of depression with five or more additional symptom criteria. Frequencies of symptoms and psychiatric and medical comorbid are provided. Substance use was more common in males, and panic disorder in females. Within pairs of affected siblings, correlations were significant for age at onset, substance abuse/dependence, panic disorder, obsessive-compulsive disorder and nicotine initiation and persistence. We replicated previously reported associations among comorbid panic disorder and social phobia, chronicity of depression and suicidal behavior. This suggests comparability of our cases to those in earlier large family studies. This dataset should prove useful for genetic studies of a highly familial form of major depressive disorder.