Identifying phenotypes for successful cognitive aging, intact cognition into late-old age (>age 75), can help identify genes and neurobiological systems that may lead to interventions against and prevention of late-life cognitive impairment. The association of C-reactive protein (CRP) with cognitive impairment and dementia, observed primarily in young-elderly samples, appears diminished or reversed in late-old age (75+ years). A family history study determined if high CRP levels in late-old aged cognitively intact probands are associated with a reduced risk of dementia in their first-degree family members, suggesting a familial successful cognitive aging phenotype.
The primary sample was 1,329 parents and siblings of 277 cognitively intact male veteran probands at least 75 years old. The replication sample was 202 relatives of 51 cognitively intact community-ascertained probands at least 85 years old. Relatives were assessed for dementia by proband informant interview. Their hazard ratio (HR) for dementia as a function of the proband's log-transformed CRP was calculated using the proportional hazards model.
Covarying for key demographics, higher CRP in probands was strongly associated with lower risk of dementia in relatives (HR = 0.55 [95% confidence interval (CI) 0.41, 0.74], p < 0.02). The replication sample relationship was in the same direction, stronger in magnitude, and also significant (HR = 0.15 [95% CI 0.06, 0.37], p < 0.0001).
Relatives of successful cognitive aging individuals with high levels of CRP are relatively likely to remain free of dementia. High CRP in successful cognitive aging individuals may constitute a phenotype for familial—and thus possibly genetic—successful cognitive aging.
Life expectancy is a familial trait. However, the effectiveness of using the age at death of a deceased parent to estimate life expectancy in their offspring can vary depending on whether death in the parent was due to extrinsic versus intrinsic causes, as well as demographic characteristics such as sex. While Alzheimer’s disease (AD) risk increases with increased age, mortality for individuals with AD is increased in contrast to comparably aged individuals without AD. Yet in most cases it is not the defining neuropathology of AD that directly terminates life but instead conditions and illnesses extrinsic to AD pathology that nevertheless have increased likelihood in its presence. For this reason, we hypothesized that offspring of AD mothers would have greater longevity than offspring of mothers without AD (insufficient numbers prevented a comparable analysis using fathers with AD). The longevity of 345 offspring of 100 deceased 60+ year old AD mothers was compared with 5,465 offspring in 1,312 deceased 60+ year old non-AD mothers. We used a proportional hazards model that accounted for clustered (nonindependent) observations due to the inclusion of several offspring from the same family. In both an unadjusted model and one that adjusted for the age at death in the mother, and the sex and birth year in the offspring we found evidence for increased longevity in the offspring of AD mothers. The results suggest that, in addition to genes that might directly affect pathways leading to AD, there may be familial/genetic factors not connected to specific pathophysiological processes in AD but instead associated with increased longevity that contribute to the familial aggregation observed in AD.
Alzheimer’s disease; longevity; familiality; life expectancy; genetics
The aim of the present study was to examine the relationship of changes in long term glucose levels as measured by Hemoglobin A1c (HbA1c) with simultaneous changes in cognition. The sample included in the present analysis consisted of 101 community dwelling non-diabetic elderly subjects participating in ongoing longitudinal studies of cognition. Subjects were included in this study if they were cognitively normal at baseline, had at least one co-temporaneous follow-up assessment of HbA1c and the Mini Mental State Exam (MMSE), and complete data on age, gender, race, and years of education. MMSE decline over time was the main outcome measure. In TOBIT mixed regression models, MMSE was the dependent variable and HbA1c the time-varying covariate. Sociodemographic (age, gender, and education), cardiovascular (hypertension and APOE4 status), and lifestyle (smoking and physical activity) covariates were included in the statistical model. After adjusting for age at follow-up, there was a decrease of 1.37 points in the MMSE (p = 0.0002) per unit increase in HbA1c. This result remained essentially unchanged after adjusting also for gender and education (p = 0.0005), cardiovascular factors (p = 0.0003), and lifestyle (p = 0.0006). Additionally, results remained very similar after excluding subjects with potentially incipient diabetes with HbA1c between 6 and 7. These findings suggest that in non-diabetic non-demented elderly subjects, an increase in HbA1c over time is associated with cognitive decline. Such results may have broad clinical applicability since manipulation of glucose control, even in non-diabetics, may affect cognitive performance, perhaps enabling preventive measures against dementia.
Cognition; elderly; glucose control; HbA1c; non-diabetic
There are very little data on the relationship between systolic blood pressure (SBP), diastolic blood pressure (DBP), arterial compliance and left ventricular structure and function, particularly left ventricular hypertrophy (LVH) in the very elderly (>75 years). SBP and arterial stiffness increase with age, and the question is: which of the two is the main stimulus to LV hypertrophy? This is a cross-sectional study to compare blood pressure and arterial stiffness measures with regard to their correlations with echocardiographic parameters of LV structure and function, controlling for age and cardiovascular risk factors, in a very elderly population. Arterial stiffness was determined by radial pulse waveform using pulse contour analysis. LV dimensions were measured by transthoracic M-mode echocardiography, and diastolic function by tissue Doppler measurements of diastolic mitral annular velocities. There were 179 subjects, all male, with a mean age of 81.8 years. Using age-adjusted partial correlations, SBP, DBP and mean arterial pressure (MAP) were correlated with parameters of LV structure and function. Correlation coefficients were: SBP v. left ventricular mass index (LVMI), r = 0.246; SBP v. early diastolic mitral annular velocity (MAV), r = -0.179; DBP v. LVMI, r = 0.199; DBP v. MAV, r = -0.199; MAP v. LVMI r = 0.276; and MAP v. MAV, r = -.206, all with p<0.05. However, neither capacitative nor reflective arterial compliance was significantly correlated with any parameter of LV structure and function. After controlling for age and ten cardiovascular and metabolic risk factors, the correlation between blood pressure and the measured LV parameters was substantially unchanged, as was the lack of correlation between indices of arterial compliance and the LV indices. Arterial blood pressure is correlated with LV structure and function in the very elderly, but arterial stiffness, as measured by diastolic pulse contour analysis, is not.
Blood pressure; blood pressure; arterial stiffness; arterial compliance; myocardial remodeling; left ventricular hypertrophy; elderly
We sought to identify cognitive phenotypes for family/genetic studies of successful cognitive aging (SCA; maintaining intact cognitive functioning while living to late old age).We administered a battery of neuropsychological tests to nondemented nonagenarians (n = 65; mean age = 93.4±3.0) and their offspring (n = 188; mean age = 66.4±5.0) from the Central Valley of Costa Rica. After covarying for age, gender, and years of education, as necessary, heritability was calculated for cognitive functions at three pre-defined levels of complexity: specific neuropsychological functions (e.g., delayed recall, sequencing), three higher level cognitive domains (memory, executive functions, attention), and an overall neuropsychological summary. The highest heritability was for delayed recall (h2 = 0.74, se = 0.14, p < 0.0001) but significant heritabilities involving memory were also observed for immediate recall (h2 = 0.50), memory as a cognitive domain (h2 = 0.53), and the overall neuropsychological summary (h2 = 0.42). Heritabilities for sequencing (h2 = 0.42), fluency (h2 = 0.39), abstraction (h2 = 0.36), and the executive functions cognitive domain (h2 = 0.35) were also significant. In contrast, the attention domain and memory recognition were not significantly heritable in these families. Among the heritable specific cognitive functions, a strong pleiotropic effect (i.e., evidence that these may be influenced by the same gene or set of genes) for delayed and immediate recall was identified (bivariate statistic = 0.934, p < 0.0001) and more modest but significant effects were found for four additional bivariate relationships. The results support the heritability of good cognitive function in old age and the utilization of several levels of phenotypes, and they suggest that several measures involving memory may be especially useful for family/genetic studies of SCA.
Family studies; hispanic population; neuropsychological phenotype; oldest-old; successful cognitive aging
Advanced glycations end products increase oxidant stress, inflammation, and neurotoxicity. Serum levels are increased in diabetes and aging. We examined the relationship between serum methylglyoxal derivatives (sMG), and cognitive decline, in 267 non-demented elderly.
Tobit mixed regression models assessed the association of baseline sMG with cognitive decline in the Mini Mental State Exam (MMSE) over time, controlling for sociodemographic factors (age, sex, and years of education), cardiovascular risk factors (diabetes and presence of an APOE4 allele), and kidney function. sMG was assessed by ELISA.
The fully adjusted model showed an annual decline of 0.26 MMSE points per unit increase in baseline sMG (p=0.03). Significance was unchanged as additional risk factors were added to the model. The interactions of sMG with diabetes, sex, age, kidney function, and APOE4 genotype were not significant.
Higher levels of baseline sMG were associated with a faster rate of cognitive decline, after adjusting for several sociodemographic and clinical characteristics. This relationship did not differ by sex, APOE4 genotype, or diabetes status suggesting its generality. Since subjects were cognitively normal at the beginning of the study, elevated sMG may be indicative of brain cell injury initiated before clinically evident cognitive compromise.
methylglyoxal; advanced glycation end products; type 2 diabetes; cognitive decline; Alzheimer's disease
Mutations in the PTEN gene are associated with a broad spectrum of disorders, including Cowden syndrome (CS), Bannayan–Riley–Ruvalcaba syndrome, Proteus syndrome, and Lhermitte–Duclos disease. In addition, PTENmutations have been described in a few patients with autism spectrum disorders (ASDs) and macrocephaly. In this study, we screened the PTEN gene for mutations and deletions in 88 patients with ASDs and macrocephaly (defined as ≥2 SD above the mean). Mutation analysis was performed by direct sequencing of all exons and flanking regions, as well as the promoter region. Dosage analysis of PTEN was carried out using multiplex ligation-dependent probe amplification (MLPA). No partial or whole gene deletions were observed. We identified a de novo missense mutation (D326N) in a highly conserved amino acid in a 5-year-old boy with autism, mental retardation, language delay, extreme macrocephaly (+9.6 SD) and polydactyly of both feet. Polydactyly has previously been described in two patients with Lhermitte–Duclos disease and CS and is thus likely to be a rare sign of PTEN mutations. Our findings suggest that PTEN mutations are a relatively infrequent cause of ASDs with macrocephaly. Screening of PTEN mutations is warranted in patients with autism and pronounced macrocephaly, even in the absence of other features of PTEN-related tumor syndromes.
Cowden syndrome; Bannayan–Riley–Ruvalcaba syndrome; polydactyly; sequence analysis; multiplex ligation-dependent probe amplification
Consistent with the clinical picture of milder symptomatology in schizotypal personality disorder (SPD) than schizophrenia, morphological studies indicate SPD abnormalities in temporal lobe regions but to a much lesser extent in prefrontal regions implicated in schizophrenia. Lower fractional anisotropy (FA), a measure of white-matter integrity within prefrontal, temporal, and cingulate regions has been reported in schizophrenia but has been little studied in SPD.
To examine temporal and prefrontal FA in 30 neuroleptic-naïve SPD patients and 35 matched healthy controls. We hypothesized that compared with healthy controls (HCs), SPD patients would exhibit lower FA in temporal and anterior cingulum regions but relative sparing in prefrontal regions.
We acquired diffusion tensor imaging (DTI) in all participants and examined FA in the white matter underlying Brodmann areas (BAs) in dorsolateral prefrontal (BA44,45,46), temporal (BA22,21,20), and cingulum (BA25,24,31,23,29) regions using multivariate-ANOVAs.
Compared with healthy controls, the SPD group had significantly lower FA in left temporal but not prefrontal regions. In the cingulum, FA was lower in the SPD group in posterior regions (BA31 and 23), higher in anterior (BA25) regions and lower overall in the right but not left cingulum. Among the SPD group, lower FA in the cingulum was associated with more severe negative symptoms (e.g., odd speech).
Similar to schizophrenia, our results indicate cingulum-temporal lobe FA abnormalities in SPD and suggest that cingulum abnormalities are associated with negative symptoms.
Diffusion tensor imaging; schizotypal personality disorder; dorsolateral prefrontal cortex; temporal lobe; cingulum; fractional anisotropy
Little is known about brain function in the oldest old, although this is the fastest growing segment of the population in developed countries and is of paramount importance in public health considerations. In this study, we investigated the cerebral response to a memory task in healthy subjects over age 90 compared with healthy younger elderly.
We studied 29 healthy elderly subjects, 12 over age 90 and 17 between age 70 and 80. All subjects were cognitively intact, as verified by a neuropsychological battery, and performed a nonverbal memory task while undergoing a functional MRI (fMRI). Activation results were analyzed by a random-effects ANCOVA using SPM5. The task resulted in activation of similar areas of the posterior temporal, parietal, and posterior frontal cortexes, but the activation was more robust in the younger subjects, especially in the right hippocampus, and parietal and temporal cortices. This finding remained after controlling for education, cognition, task performance or cerebral atrophy.
The phenomenon of relatively maintained performance, despite significant brain atrophy and lower activation is consistent with the cognitive reserve theory and may be specific to subjects with extremely successful aging. Further investigation of brain activation patterns in the oldest old is warranted.
functional MRI; nonagenarians; brain activation; cognitive reserve
schizophrenia; 5p13; AMACR; genetic association; case-control study
In cross-sectional and longitudinal studies, type 2 diabetes has been positively associated with the risk of Alzheimer’s disease (AD). The present descriptive study compared diabetic and nondiabetic subjects on the severity of neuritic plaques and neurofibrillary tangles (NFTs) in the cerebral cortex and in the hippocampus.
The study included specimens from 385 consecutive autopsies of residents of a nursing home (15.8% diabetics). Mean age at death = 84 years [standard deviation (SD) = 10], 66% were female, Clinical Dementia Rating mean = 3.0 (SD = 1.6), and 32.5% had an APOE4 allele. Additional analyses limited the sample to 268 subjects (14.1% diabetics) without neuropathology other than AD.
Analyses of covariance controlling for age at death, dementia severity (Clinical Dementia Rating score), and APOE4 allele indicated that diabetics had significantly fewer neuritic plaques (p = .008) and NFTs (p = .047) in the cerebral cortex than did nondiabetics. In the hippocampus, diabetics had significantly lower plaque ratings than did nondiabetics (p = .019), but the lower ratings of NFTs did not achieve statistical significance (p = .082). In the entire sample, diabetics had significantly less AD-associated neuropathology in all four analyses.
These results raise the possibility that the varied associations observed between diabetes and AD may be specific to as yet ill-defined subgroups of dementia and diabetic patients or may be more characteristic of younger patients than of those who survive to a mean age of 84 years. Future studies are encouraged to examine a variety of other characteristics such as age that may interact with diabetes affecting the incidence of AD.
Structural and functional brain reserves, thought to develop in childhood and adolescence, may be critical in determining the age at onset of cognitive impairment. Body height is affected by childhood conditions that promote growth. The authors examine the relationship of height in midlife and subsequent dementia, Alzheimer disease (AD), and vascular dementia.
Dementia was evaluated from 1999 to 2001 in 1,892 men age 76 to 95. Height had been measured when these men participated in the Israeli Ischemic Heart Disease project in 1963. Age, socioeconomic status (SES), and area of birth were also assessed in 1963.
Older men and those with lower SES tended to be shorter. Relative to the shortest quartile, controlling for age, SES, and area of birth, the other quartiles had lesser respective odds ratios for dementia as a whole, AD, and vascular dementia.
Height was inversely associated with dementia, AD, and vascular dementia in a male sample. Since height is associated with childhood nutrition and may be associated with other risk factors for dementia, efforts to improve early life conditions that maximize body growth may diminish or delay the onset of dementia in later life.
To assess the relationships between early and late antemortem measures of dementia severity and Alzheimer disease (AD) neuropathology severity.
40 residents of a nursing home, average age at death 82.0, participated in this longitudinal cohort study with postmortem assessment. Severity of dementia was measured by Clinical Dementia Rating (CDR) at two time points, averaging 4.5 and 1.0 years before death. Densities of postmortem neuritic plaques (NPs) and neurofibrillary tangles (NFTs) were measured in the cerebral cortex, hippocampus, and entorhinal cortex.
For most brain areas, both early and late CDRs were significantly associated with NPs and NFTs. CDRs assessed proximal to death predicted NFTs beyond the contribution of early CDRs. NPs were predicted by both early and late CDRs. NPs were predictive of both early and late CDRs after controlling for NFTs. NFTs were only associated significantly with late CDR in the cerebral cortex after controlling for NPs.
Even if assessed several years before death, dementia severity is associated with AD neuropathology. NPs are more strongly associated with dementia severity than NFTs. NFTs consistently associate better with late than early CDR, suggesting that these neuropathological changes may occur relatively later in the course of the disease.
Dementia severity; Alzheimer’s disease; Neuropathology; Neuritic plaques; Neurofibrillary tangles
As life expectancy in the United States continues to increase, the projected numbers of elderly people who will develop dementia will grow rapidly This paper reviews four well-established cardiovascular risk factors (type 2 diabetes, hypertension, cholesterol, and inflammation), for which there is longitudinal epidemiological evidence of increased risk of dementia, Alzheimer’s disease, mild cognitive impairment, and cognitive decline. These risk factors are of special interest because of their potential modifiability, which may affect the course of cognitive compromise. Diabetes is the cardiovascular risk factor (CvRF) most consistently associated with cognition. Hypertension in midlife is consistently associated with cognition, but its associations with late-life hypertension are less clear. Total cholesterol is not consistently associated with cognition, lnterleukin-6 and C-reactive protein are inflammatory markers relatively consistently associated with cognition. Composites of the CvRFs increase the risk for dementia in a dose-dependent fashion, suggesting a cumulative effect of these factors on neuronal stress. In the relatively few studies that have reported interactions of risk factors, they potentiate each other. The effect of each of these risk factors varies according to apolipoprotein E genotype. It may be that the effect of these risk factors varies according to the presence of the others, and these complex relationships underlie the biological mechanisms of cognitive compromise. This may be crucial for understanding the effects on cognition of drugs and other approaches, such as lifestyle change, for treating these risk factors.
diabetes; hypertension; cholesterol; inflammation; dementia; Alzheimer’s disease; mild cognitive impairment; cognitive decline
This study was conducted to examine the relationship between whole blood serotonin level and behavioral symptoms in 78 subjects with autism. No significant associations were found between serotonin level and the primary behavioral outcome measures. However, a significant inverse relationship between serotonin level and self-injury was demonstrated.
autism; serotonin; repetitive behavior; self-injury; aggression
Ejection fractions; left atrial diameter; cognitive functioning; oldest old; APOE genotype
The aim of the study was to examine the association of religious education and observance with dementia among participants in the Israeli Ischemic Heart Disease study.
Study Design and Setting
We assessed dementia in 1,890 participants among 2,604 survivors of 10,059 participants in the Israeli Ischemic Heart Disease study, a longitudinal investigation of the incidence and risk factors for cardiovascular disease among Jewish male civil servants in Israel. Face-to-face interviews were conducted with 651 subjects identified as possibly demented by the Modified Telephone Interview for Cognitive Status.
Of 1,628 subjects included in this analysis (mean age 82 at assessment), 308 (18.9%) had dementia. The prevalence rates of dementia (and odds ratios (ORs) relative to those with exclusively religious education, adjusted for age, area of birth, and socioeconomic status) were 27.1% for those with exclusively religious education, 12.6% (OR=0.49) for those with mixed education, and 16.1% (OR=0.76) for those with secular education. For religious self-definition and practice, the prevalence rates were 9.7%, 17.7%, 14.1%, 19.3%, and 28.8% for categories from least to most religious (ORs relative to the most religious: 0.43, 0.67, 0.48, 0.55).
Examining lifestyles associated with religiosity might shed light onto environmental risks for dementia. Mechanisms underlying these associations remain elusive.
Religion; Dementia; Life style; Education; Risk factors; Prevalence
Schizophrenia, a devastating psychiatric disorder, has a prevalence of 0.5–1%, with high heritability (80–85%) and complex transmission.1 Recent studies implicate rare, large, high-penetrance copy number variants (CNVs) in some cases2, but it is not known what genes or biological mechanisms underlie susceptibility. Here we show that schizophrenia is significantly associated with single nucleotide polymorphisms (SNPs) in the extended Major Histocompatibility Complex (MHC) region on chromosome 6. We carried out a genome-wide association study (GWAS) of common SNPs in the Molecular Genetics of Schizophrenia (MGS) case-control sample, and then a meta-analysis of data from the MGS, International Schizophrenia Consortium (ISC) and SGENE datasets. No MGS finding achieved genome-wide statistical significance. In the meta-analysis of European-ancestry subjects (8,008 cases, 19,077 controls), significant association with schizophrenia was observed in a region of linkage disequilibrium on chromosome 6p22.1 (P = 9.54 × 10−9). This region includes a histone gene cluster and several immunity-related genes, possibly implicating etiologic mechanisms involving chromatin modification, transcriptional regulation, auto-immunity and/or infection. These results demonstrate that common schizophrenia susceptibility alleles can be detected. The characterization of these signals will suggest important directions for research on susceptibility mechanisms.
The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) was funded by the National Institute on Aging in 1986 to develop standardized, validated measures for the assessment of Alzheimer’s disease (AD). The present report describes the measures that CERAD developed during its first decade, and their continued use in their original and translated forms. These measures include clinical, neuropsychological, neuropathological and behavioral assessments of AD, and also assessment of family history and parkinsonism in AD. An approach to evaluating neuroimages did not meet the standards desired. Further evaluations which could not be completed because of lack of funding (but where some materials are available), include evaluation of very severe AD, and of service use and need by patient and caregiver. The information that was developed in the U.S. and abroad permits standardized assessment of AD in clinical practice, facilitates epidemiological studies, and provides information valuable for individual and public health planning. CERAD materials and data remain available for those wishing to use them.
Consortium to Establish a Registry for Alzheimer’s Disease; CERAD; Alzheimer’s disease; clinical assessment; neuropsychological assessment; neuropathological assessment; norms; prevalence; incidence
As life expectancy in the United States continues to increase, the projected numbers of elderly people who will develop dementia will grow rapidly. This paper reviews four well-established cardiovascular risk factors (type 2 diabetes, hypertension, cholesterol, and inflammation), for which there is longitudinal epidemiological evidence of increased risk of dementia, Alzheimer's disease, mild cognitive impairment, and cognitive decline. These risk factors are of special interest because of their potential modif lability, which may affect the course of cognitive compromise. Diabetes is the cardiovascular risk factor (CvRF) most consistently associated with cognition. Hypertension in midlife is consistently associated with cognition, but its associations with late-life hypertension are less clear. Total cholesterol is not consistently associated with cognition, interleukin-6 and C-reactive protein are inflammatory markers relatively consistently associated with cognition. Composites of the CvRFs increase the risk for dementia in a dose-dependent fashion, suggesting a cumulative effect of these factors on neuronal stress. In the relatively few studies that have reported interactions of risk factors, they potentiate each other. The effect of each of these risk factors varies according to apolipoprotein E genotype, it may be that the effect of these risk factors varies according to the presence of the others, and these complex relationships underlie the biological mechanisms of cognitive compromise. This may be crucial for understanding the effects on cognition of druqs and other approaches, such as lifestyle chanqe, for treatinq these risk factors.
diabetes; hypertension; cholesterol; inflammation; dementia; Alzheimer's disease; mild cognitive impairment; cognitive decline
While the oldest old are the fastest growing segment of the US population, normative neuropsychological data for nondemented oldest old Spanish speakers are nonexistent. This study sought to evaluate the neuropsychological performance of nondemented nonagenarians residing in Puerto Rico and to compare their results with those of a similar English-speaking sample from New York.
We studied 81 subjects who had a complete CERAD neuropsychological assessment in Spanish. We used multiple regression analysis to predict performance on the CERAD battery and ANCOVA to compare the Puerto Rico and New York samples.
In 10 out of the 13 neuropsychological tests administered, education was a significant predictor of performance. There were significant differences between the Puerto Rico and New York groups only in the Trail Making Tests.
In this Puerto Rican sample, education was the strongest predictor of neuropsychological performance, which is consistent with previous studies. When education level is properly accounted for, the performance of Puerto Rican nonagenarians in the CERAD battery does not differ from the performance of US English-speaking nonagenarians.
Successful cognitive aging; Puerto Rican nonagenarians; Oldest old population
We have used a custom 1,536-SNP array to interrogate 94 functionally relevant candidate genes for schizophrenia and identify associations with 12 heritable neurophysiological and neurocognitive endophenotypes collected as part of the Consortium on the Genetics of Schizophrenia (COGS).
Variance-component association analyses of 534 genotyped subjects from 130 families were conducted using Merlin. A novel bootstrap Total Significance Test was also developed to overcome the limitations of existing genomic multiple testing methods and robustly demonstrate the presence of significant associations in the context of complex family data and possible population stratification effects.
Associations were observed for 46 genes of potential functional significance with 3 SNPs at p<10−4, 27 SNPs at p<10−3, and 147 SNPs at p<0.01. The bootstrap analyses confirmed that the 47 SNP-endophenotype combinations with the strongest evidence of association significantly exceeded (p=0.001) that expected by chance alone with 93% of these findings expected to be true. Many of the genes interact on a molecular level, and eight genes displayed evidence for pleiotropy (e.g., NRG1 and ERBB4), revealing associations with four or more endophenotypes. Our results collectively support a strong role for genes related to glutamate signaling in mediating schizophrenia susceptibility.
This study supports the use of relevant endophenotypes and the bootstrap Total Significance Test for the identification of genetic variation underlying the etiology of schizophrenia. In addition, the observation of extensive pleiotropy for some genes and singular associations for others in our data suggests alternative, independent pathways mediating pathogenesis in the “group of schizophrenias”.