The kidney and brain expressed protein gene (KIBRA) and the calsyntenin 2 gene (CLSTN2) are reportedly involved in synaptic plasticity. Single nucleotide polymorphisms (SNPs) rs17070145 (KIBRA) and rs6439886 (CLSTN2) have been found to affect memory performance measures. This study examined the association of KIBRA SNP rs17070145 and CLSTN2 SNPs rs6439886 and rs17348572 (a nonsynonymous variant) with cognitive flexibility in 674 African Americans (AAs; 526 current smokers) and 419 European Americans (EAs; 318 current smokers). The subjects’ cognitive flexibility was assessed using the Wisconsin Card Sorting Test. The effects on cognitive flexibility of sex, age, education, and tobacco recency (a possible mediator of gene effects in smokers), the three SNPs, and the interaction of each SNP with tobacco recency were analyzed using multivariate analysis of variance. In AAs, there were no main or interaction effects of the SNPs on cognitive flexibility. In EAs, the two CLSTN2 SNPs showed no main effect on cognitive flexibility. However, among EAs, individuals with the KIBRA rs17070145 T allele made significantly more perseverative responses (P=0.002) and perseverative errors (P=0.002) than those with no T allele. Furthermore, among EAs with the rs17070145 T allele, current smokers made significantly fewer perseverative responses (P<0.001) and perseverative errors (P<0.001) than past smokers. Nongenetic factors (age, education, and tobacco recency) had substantial effects on cognitive flexibility in both AAs and EAs. We conclude that variation in KIBRA influences cognitive flexibility in a population-specific way, and that current smoking status moderates this effect.
KIBRA; CLSTN2; cognitive flexibility; Wisconsin Card Sorting Test; single nucleotide polymorphism; SNP × tobacco recency
The human KIBRA gene has been linked to human cognition through a lead intronic single-nucleotide polymorphism (SNP; rs17070145) that is associated with episodic memory performance and the risk to develop Alzheimer's disease. However, it remains unknown how this relates to the function of the KIBRA protein. Here, we identified two common missense SNPs (rs3822660G/T [M734I], rs3822659T/G [S735A]) in exon 15 of the human KIBRA gene to affect cognitive performance, and to be in almost complete linkage disequilibrium with rs17070145. The identified SNPs encode variants of the KIBRA C2 domain with distinct Ca2+ dependent binding preferences for monophosphorylated phosphatidylinositols likely due to differences in the dynamics and folding of the lipid-binding pocket. Our results further implicate the KIBRA protein in higher brain function and provide direction to the cellular pathways involved.
C2 domain; human cognition; KIBRA; membrane binding; phosphatidylinositols
We recently reported evidence for an association between the individual variation in normal human episodic memory and a common variant of the KIBRA gene, KIBRA rs17070145 (T-allele). Since memory impairment is a cardinal clinical feature of Alzheimer’s disease (AD), we investigated the possibility of an association between the KIBRA gene and AD using data from neuronal gene expression, brain imaging studies, and genetic association tests. KIBRA was significantly over-expressed and 3 of its 4 known binding partners under-expressed in AD-affected hippocampal, posterior cingulate and temporal cortex regions (p<0.010, corrected) in a study of laser capture microdissected neurons. Using positron emission tomography in a cohort of cognitively normal, late-middle-aged persons genotyped for KIBRA rs17070145, KIBRA T non-carriers exhibited lower glucose metabolism than did carriers in posterior cingulate and precuneus brain regions (P<0.001, uncorrected). Lastly, non-carriers of the KIBRA rs17070145 T-allele had increased risk of late-onset AD in an association study of 702 neuropathologically verified expired subjects (p=0.034; OR=1.29) and in a combined analysis of 1026 additional living and expired subjects (p=0.039; OR=1.26). Our findings suggest that KIBRA is associated with both individual variation in normal episodic memory and predisposition to AD.
genetics; imaging; expression profiling; memory
The rs17070145 polymorphism (C → T substitution, intron 9) of the KIBRA gene has recently been associated with episodic memory and cognitive flexibility. These findings were inconsistent across reports though, and largely lacked gene–gene or gene–environment interactions. The aim of the present study was to determine the impact of the rs17070145 polymorphism on clinically relevant cognitive domains and its interaction with the modifiers ‘lifestyle' and ‘cardiovascular risk factors'. Five-hundred forty-five elderly volunteers (mean age 64 years, ±7 years, 56% women) accomplished a comprehensive cognitive testing. Principal component analysis was used to reveal the internal structure of the data, rendering four composite scores: verbal memory, word fluency, executive function/psychomotor speed, and working memory. Lifestyle was assessed with a detailed questionnaire, age-associated risk factors by clinical interview and examination. There was no main effect of the rs17070145 genotype on any cognitive composite scores. However, we found worse performance in executive functions for T-allele carriers in the presence of arterial hypertension (β=−0.365, p=0.0077 and 0.031 after Bonferroni correction). This association was further modified by gender, showing the strongest association in hypertensive females (β=−0.500, p=0.0072 and 0.029 after Bonferroni correction). The effect of KIBRA on cognitive function seems to be complex and modified by gender and arterial hypertension.
aging; memory; executive functions; vascular risk factors; gender; ecogenetic context; Aging; memory; executive functions; vascular risk factors; gender; ecogenetic context
The kidney and brain protein (KIBRA) is a scaffold or an adaptor-like protein with WW, C2-like and atypical protein kinase C (aPKC)-binding domains. Genetic studies in Drosophila revealed that KIBRA is an upstream regulator of the conserved Hippo pathway, which is implicated in organ size determination. In addition, genome-wide studies revealed an association between the single nucleotide polymorphism in the KIBRA gene locus and human episodic memory performance. However, the mechanism of action through which KIBRA is linked to these functions remains poorly understood. Recent studies on the biochemical and cellular properties of KIBRA reveal the role of KIBRA as a regulator of membrane trafficking. Further, KIBRA directly inhibits the activity of the cell polarity regulator, aPKC, which is required for apical protein exocytosis. Here, we discuss how this KIBRA-aPKC connection, a potential regulator of membrane trafficking and cell polarity, can contribute to the recently discovered functions of KIBRA.
atypical PKC; cell polarity; Hippo pathway; KIBRA; membrane trafficking; memory formation
KIBRA has recently been identified as a gene associated with human memory performance. Despite the elucidation of the role of KIBRA in several diverse processes in non-neuronal cells, the molecular function of KIBRA in neurons is unknown. We found that KIBRA directly binds to the protein interacting with C-kinase 1 (PICK1) and forms a complex with α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors (AMPARs), the major excitatory neurotransmitter receptors in the brain. KIBRA knockdown accelerates the rate of AMPAR recycling following N-methyl-D-aspartate receptor induced internalization. Genetic deletion of KIBRA in mice impairs both long-term depression and long-term potentiation at hippocampal Schaffer collateral-CA1 synapses. Moreover, KIBRA knockout mice have severe deficits in contextual fear learning and memory. These results indicate that KIBRA regulates higher brain function by regulating AMPAR trafficking and synaptic plasticity.
A recent study suggested that the insertion (I) allele in intron 16 of the angiotensin converting enzyme gene (ACE) is associated with Alzheimer's disease (AD) risk. In our series of 239 necropsy confirmed late onset AD cases and 342 elderly non-demented controls aged >73 years, we found significantly different ACE genotype distributions in the case and control groups (p=0.007). Homozygotes for both the I and D alleles were associated with a higher risk compared to DI heterozygotes. While the APOE ε4 allele was strongly associated with AD risk in our series, we found no evidence for an interaction between the APOE and ACE loci. In addition, no interactions were observed between ACE and gender or age at death of the AD cases. A meta-analysis of all published reports (12 case-control series in total) suggested that both the II and ID ACE genotypes are associated with increased AD risk (odds ratio (OR) for II v DD 1.36, 95% confidence interval (CI)=1.13-1.63, OR for DI v DD 1.33, 95% CI=1.14-1.53, p=0.0002).
Keywords: Alzheimer's disease; ACE gene; I allele
The Salvador (Sav)/Warts (Wts)/Hippo (Hpo) (SWH) network controls tissue growth by inhibiting cell proliferation and promoting apoptosis. The core of the pathway consists of a MST and LATS family kinase cascade that ultimately phosphorylates and inactivates the YAP/Yorkie (Yki) transcription coactivator. The FERM domain proteins Merlin (Mer) and Expanded (Ex) represent one mode of upstream regulation controlling pathway activity. Here, we identify Kibra as a member of the SWH network. Kibra, which colocalizes and associates with Mer and Ex, also promotes the Mer/Ex association. Furthermore, the Kibra/Mer association is conserved in human cells. Finally, Kibra complexes with Wts and kibra depletion in tissue culture cells induces a marked reduction in Yki phosphorylation without affecting the Yki/Wts interaction. We suggest that Kibra is part of an apical scaffold that promotes SWH pathway activity.
► The Salvador/Hippo/Warts network restricts tissue size ► We identify the scaffold protein Kibra as a SWH upstream regulator ► Kibra promotes SWH activity by complexing with multiple pathway members
SIGNALING; CELLBIO; DEVBIO
Previously, utilizing a series of genome-wide association, brain imaging and gene expression studies we implicated the KIBRA gene and the RhoA/ROCK pathway in hippocampal-mediated human memory. Here we show that peripheral administration of the ROCK inhibitor hydroxyfasudil improves spatial learning and working memory in the rodent model. This study supports the action of ROCK on learning and memory, suggests the potential value of ROCK inhibition for the promotion of cognition in humans and highlights the powerful potential of unbiased genome-wide association studies to inform potential novel uses for existing pharmaceuticals.
learning; memory; ROCK; fasudil; aging
Existing evidence suggests that psychosocial stress is associated with cognitive impairment in older adults. Perceived discrimination is a persistent stressor in African Americans that has been associated with several adverse mental and physical health outcomes. To our knowledge, the association of discrimination with cognition in older African Americans has not been examined. In a cohort of 407 older African Americans without dementia (mean age = 72.9; SD = 6.4), we found that a higher level of perceived discrimination was related to poorer cognitive test performance, particularly episodic memory (estimate = −0.03; SE = .013; p < .05) and perceptual speed tests (estimate = −0.04; SE = .015; p < .05). The associations were unchanged after adjusting for demographics and vascular risk factors, but were attenuated after adjustment for depressive symptoms (Episodic memory estimate = −0.02; SE = 0.01; Perceptual speed estimate = −0.03; SE = 0.02; both p’s = .06). The association between discrimination and several cognitive domains was modified by level of neuroticism. The results suggest that perceived discrimination may be associated with poorer cognitive function, but does not appear to be independent of depressive symptoms.
African American; Cognitive function; Epidemiology; Psychological stress; Depressive symptoms; Cohort study
The genetic locus encoding KIBRA, a member of the WWC family of proteins, has recently been shown to be associated with human memory performance through genome-wide single nucleotide polymorphism screening. Gene expression analysis and a variety of functional studies have further indicated that such a role is biologically plausible for KIBRA. Here, we review the existing literature, illustrate connections between the different lines of evidence, and derive models based on KIBRA's function(s) in the brain that can be further tested experimentally.
cognition; memory; hippocampus; genome-wide association study (GWAS); Alzheimer's disease; cognitive impairment; PKCζ
Exposure to nicotine in tobacco smoke during development has been linked to subsequent deficits in attention and memory. The present study tested for evidence that genetic variation may contribute to individual differences in vulnerability to the effects of developmental exposure to tobacco smoke on memory and medial temporal lobe function in adolescents.
Verbal and visuospatial memory were assessed and functional magnetic resonance imaging (fMRI) data were acquired in 101 adolescents systematically characterized for prenatal and adolescent exposure to tobacco smoke, while they performed an encoding and recognition memory task. The impact of allelic variation at loci within CLSTN2 (encoding synaptic protein calsyntenin 2) and KIBRA, shown previously to modulate early and delayed recall of words, on the dependent measures was examined.
KIBRA genotype did not exert significant main or interacting effects with prenatal or adolescent exposure to tobacco smoke on verbal or visuospatial memory. Previous observations of a beneficial effect of the CLSTN2 C allele on verbal recall were replicated. Adolescent exposure to tobacco smoke reversed this beneficial effect and was associated with increased activation of parahippocampal gyrus during early and delayed recognition in CLTSN2 C allele carriers. While the CLSTN2 C allele conferred enhanced functional connectivity between brain regions subserving accurate verbal recognition, adolescent exposure to tobacco smoke reversed this effect.
These findings extend previous work demonstrating that calsyntenins play an essential role in learning and indicate that this role is modulated both by CLSTN2 genotype and, during adolescent development, by exposure to tobacco smoke.
Adolescent; calsyntenin 2; nicotine; parahippocampal gyrus; prenatal; verbal memory
The role of inflammation is being considered in chronic diseases. Previous studies have examined SNPs in a few key inflammatory genes and have included small numbers of African American participants. Variation in the frequencies of inflammatory pathway SNPs may help to explain racial disparities in disease risk. Through a population-based study of 103 African American and 380 Caucasian unrelated, healthy women, we examined the relationships between race and allele frequencies of 70 cytokine and cytokine receptor SNPs. The associations between genotypic and haplotype frequencies and race were also analyzed. Allelic frequencies for 52 out of the 70 SNPs meeting criteria for analysis differed significantly by race. Of the 32 pro-inflammatory and 20 anti-inflammatory SNPs for which the allele frequencies varied significantly by race, variant allele frequency differences between Caucasians and African Americans ranged between 6%–37% and 7%–53% for pro-inflammatory SNPs and anti-inflammatory SNPs, respectively. Our findings suggest that while allele frequencies do vary by race, racial groups are not simplistically represented by a pro-inflammatory or anti-inflammatory genetic profile. Given the racial variability in allele frequencies in inflammatory gene SNPs, studies examining the association between these SNPs and disease should at least incorporate self-reported race in their analyses.
Cytokines; SNPs; Racial Differences; Women
Variants in 3′ and 5′ regions of SORL1, the neuronal sorting protein-related receptor, were recently found to be associated with late onset familial and sporadic Alzheimer’s disease in several datasets that were selected for familial aggregation or were ethnically diverse or clinic-based selected series.
To investigate the association between Alzheimer’s disease and variant alleles in SORL1 using a series of single nucleotide polymorphisms (SNPs) in an urban, multiethnic community-based population.
Design & Setting
We used a nested case-control analysis in a population-based, prospective study of aging and dementia in Medicare recipients, 65 years and older, residing in northern Manhattan.
There were 296 patients with probable Alzheimer’s disease and 428 healthy elderly controls. The participants were of African American (34%), Caribbean Hispanic (51%) or non-Hispanic whites (15%).
Main Outcome Measures
We genotyped all 29 SNPs in SORL1 that were examined in the earlier report. We assessed allelic association with AD using standard case-control methods which included APOE genotype as a covariate.
Several individual SNPs and SNP haplotypes were significantly associated with AD in this prospectively collected community-based cohort, confirming the previously reported positive association of SORL1 with Alzheimer’s disease. SNP 12 near the 5′ region was associated with AD in African-Americans and Hispanics. Two SNPs in the 3′ region were also associated with AD in African-Americans (SNP 26) and Whites (SNP 20). A single haplotype in the 3′ region was associated with AD in Hispanics. However, several different haplotypes were associated with AD in the African-Americans and Whites, including the “TTC” haplotypes at SNPs 23–25 (p=0.035) that was significantly associated with AD in the North European Whites in the previous report.
This study confirms the association between genetic variants in SORL1 and AD. While the associations observed in these datasets overlap with those previously reported, the finding of novel SNP and haplotype associations suggest that there may be extensive allelic heterogeneity in SORL1. Broad regions of the SORL1 gene will therefore need to be scrutinized for functional pathogenic variants.
SORL1; Alzheimer’s disease; sporadic; African American; Caribbean Hispanic
A role for the immune system in the pathogenesis of Parkinson’s Disease (PD) has previously been suggested. A recent genome-wide association (GWA) study identified an association between one single nucleotide polymorphism (SNP) in the human leucocyte antigen (HLA) region (HLA-DRA rs3129882) and PD in a population of American patients with European ancestry. In that study, the minor rs3129882 allele (G) was associated with an increased risk of PD under an additive model. Due to the increased likelihood of obtaining false positive results in GWA studies compared to studies conducted based on a hypothesis-driven approach, repeated validation of findings from GWA studies are necessary. Herein, we evaluated the association between rs3129882 and PD in three different Caucasian patient-control series (combined 1,313 patients and 1,305 controls) from the US, Ireland, and Poland. We observed no association (OR: 0.96, P=0.50) between rs3129882 and PD when analyzing our data under an additive or dominant model. In contrast, when examined under a recessive model, the GG genotype was observed to be protective in the Irish (OR: 0.55, P=0.008), Polish (OR: 0.67, P=0.040) and combined (OR: 0.75, P=0.006) patient-control series. In view of these diverging results, the exact role of genetic variation at the HLA region and susceptibility to PD remains to be resolved.
Association studies; Parkinson’s disease; Human leukocyte antigen; HLA; HLA-DRA; Immune system; Genetics
Recent genome-wide association studies (GWAS) have identified multiple common genetic risk variants for breast cancer among women of Asian and European ancestry. Investigating these genetic susceptibility loci in other populations would be helpful to evaluate the generalizability of the findings and identify causal variants for breast cancer. We evaluated 11 GWAS-identified genetic susceptibility loci for breast cancer in a study including 2,594 African-American women (810 cases and 1,784 controls). Two single-nucleotide polymorphisms (SNPs), rs13387042 (2q35) and rs1219648 (FGFR2 gene), were found to be associated with breast cancer risk. Risk increased nearly linearly with number of affected risk alleles, with a two-fold elevated risk for women homozygous for the risk alleles in both SNPs. No additional significant associations, however, were identified for the other 9 loci evaluated in the study. The results from this study extend some of the recent GWAS findings to African Americans and may guide future efforts to identify causal variants for breast cancer.
The apolipoprotein E (APOE) ∊4 allele is a well-known risk factor for the development of Alzheimer's disease, but little is known about the association of the ∊4 allele with incident mild cognitive impairment (MCI).
Test the hypothesis that the ∊4 allele is associated with an increased risk of developing MCI.
More than 600 older Catholic clergy members from the Religious Orders Study without any cognitive impairment at baseline underwent APOE genotyping and detailed annual clinical evaluations for up to 16 years of follow-up (mean: 10.17 years; range: 2–16 years) to document incident MCI and rates of decline in global cognition and 5 cognitive domains (i.e. episodic memory, semantic memory, working memory, perceptual speed and visuospatial abilities).
During up to 16 years of annual follow-up, 339 of 607 persons (56%) developed MCI. In a proportional hazards model adjusted for age, sex and education, the presence of the APOE ∊4 allele was associated with a 1.4-fold increased risk of incident MCI (hazard ratio: 1.36; 95% CI: 1.04, 1.78). Further, this association persisted in analyses that required MCI to persist for at least one year (hazard ratio: 1.50; 95% CI: 1.05, 2.14). Finally, the ∊4 allele was associated with an increased rate of decline in global cognition and 4 out of 5 cognitive systems (i.e. episodic memory, semantic memory, working memory and perceptual speed).
The presence of the APOE ∊4 allele is associated with an increased risk of MCI and a more rapid rate of cognitive decline in old age.
Apolipoprotein E; Mild cognitive impairment; Aging; Alzheimer's disease, preclinical
Large genome-wide association studies (GWAS) have identified many novel genes influencing Alzheimer disease (AD) risk, but most of the genetic variance remains unexplained. We conducted a two-stage GWAS for AD-related quantitative measures of hippocampal volume (HV), total cerebral volume (TCV), and white matter hyperintensities (WMH).
Brain MRI measures of HV, TCV and WMH were obtained from 981 Caucasian and 419 African American AD cases and their cognitively normal siblings in the MIRAGE Study, and from 168 AD cases, 336 individuals with mild cognitive impairment and 188 controls in the ADNI Study. A GWAS for each trait was conducted in the two Caucasian datasets in stage 1. Results from the two datasets were combined by meta analysis. In stage 2, one SNP from each region that was nominally significant in each dataset (p<0.05) and strongly associated in both datasets (p<1.0×10−5) was evaluated in the African American dataset.
Twenty-two markers (14 for HV, 3 for TCV, and 5 for WMH) from distinct regions met criteria for evaluation in stage 2. Novel genome-wide significant associations (p<5.0×10−8) were attained for HV with SNPs in the APOE, F5/SELP, LHFP and GCFC2 gene regions. All of these associations were supported by evidence in each dataset. Associations with different SNPs in the same gene (p<1×10−5 in Caucasians and p<2.2×10−4 in African Americans) were also observed for PICALM with HV, SYNPR with TCV and TTC27 with WMH.
Our study demonstrates the efficacy of endophenotypes for broadening our understanding of the genetic basis of AD.
In vitro and animal model studies suggest that transthyretin (TTR) inhibits the production of the amyloid β protein, a major contributor to Alzheimer disease (AD) pathogenesis. We evaluated the association of 16 TTR single nucleotide polymorphisms (SNPs) with AD risk in 158 African American and 469 Caucasian discordant sibships from the MIRAGE Study. There was no evidence for association of TTR with AD in either population sample. To examine the possibility that TTR SNPs affect specific components of the AD process, we tested association of these SNPs with four measures of neurodegeneration and cerebrovascular disease defined by magnetic resonance imaging (MRI) in a subset of 48 African American and 265 Caucasian sibships. Five of seven common SNPs and several haplotypes were significantly associated with hippocampal atrophy in the Caucasian sample. Two of these SNPs also showed marginal evidence for association in the African American sample. Results for the other MRI traits were unremarkable. This study highlights the potential value of neuroimaging endophenotypes as a tool for finding genes influencing AD pathogenesis.
Interferon regulatory factor 2 (IRF2) is a member of a family of transcriptional factors involved in the modulation of interferon induced immune responses to viral infection. To test whether genetic variants in IRF2 predict risk of AD and ADEH, we genotyped 78 IRF2 tagging single nucleotide polymorphisms (SNPs) in both European American (n=435) and African American (n = 339) populations. Significant associations were observed between AD and two SNPs (rs793814, P = 0.007, odds ratio (OR) = 0.52; rs3756094, P = 0.037, OR = 0.66) among European Americans and one SNP (rs3775572, P = 0.016, OR = 0.46) among African Americans. Significant associations were also observed between ADEH and five SNPs (P = 0.049-0.022) among European Americans. The association with ADEH was further strengthened by haplotype analyses, wherein a 5-SNP (CAGGA) haplotype showed the strongest association with ADEH (P = 0.0008). Eight IRF2 SNPs were significantly associated with IFNγ production post-herpes simplex virus (HSV) stimulation (P = 0.048-0.0008), including an AD-associated SNP (rs13139310, P = 0.008). Our findings suggest distinct markers in IRF2 may be associated with AD and ADEH, which may depend upon ethnic ancestry, and genetic variants in IRF2 may contribute to an abnormal immune response to HSV.
Complement receptor 1 (CR1) is an Alzheimer's disease (AD) susceptibility locus that also influences AD-related traits such as episodic memory decline and neuritic amyloid plaque deposition. We implemented a functional fine-mapping approach, leveraging intermediate phenotypes to identify functional variant(s) within the CR1 locus. Using 1709 subjects (697 deceased) from the Religious Orders Study and the Rush Memory and Aging Project, we tested 41 single-nucleotide polymorphisms (SNPs) within the linkage disequilibrium block containing the published CR1 AD SNP (rs6656401) for associations with episodic memory decline, and then examined the functional consequences of the top result. We report that a coding variant in the LHR-D (long homologous repeat D) region of the CR1 gene, rs4844609 (Ser1610Thr, minor allele frequency = 0.02), is associated with episodic memory decline and accounts for the known effect of the index SNP rs6656401 (D′ = 1, r2= 0.084) on this trait. Further, we demonstrate that the coding variant's effect is largely dependent on an interaction with APOE-ɛ4 and mediated by an increased burden of AD-related neuropathology. Finally, in our data, this coding variant is also associated with AD susceptibility (joint odds ratio = 1.4). Taken together, our analyses identify a CR1 coding variant that influences episodic memory decline; it is a variant known to alter the conformation of CR1 and points to LHR-D as the functional domain within the CR1 protein that mediates the effect on memory decline. We thus implicate C1q and MBL, which bind to LHR-D, as likely targets of the variant's effect and suggest that CR1 may be an important intermediate in the clearance of Aβ42 particles by C1q.
Alzheimer’s disease (AD) impairs olfaction, but it is uncertain how early this occurs in the disease process and whether the effect can be accounted for by other behavioral or genetic markers of the disease. We administered the Brief Smell Identification Test (BSIT) to 471 older people without dementia or cognitive impairment who then completed annual clinical evaluations and brain autopsy at death. BSIT score was associated with more rapid decline in episodic memory and with increased risk of developing incident mild cognitive impairment (MCI), even after controlling for baseline level of episodic memory and possession of an apolipoprotein E ε4 allele. In 34 people who died without evidence of cognitive impairment, lower BSIT score was associated with higher level of AD pathology, even after controlling for ε4 and for level of episodic memory function when olfaction was assessed. These analyses suggest that among older people without clinical manifestations of AD or MCI, olfactory dysfunction is related to both the level of AD pathology in the brain and the risk of subsequently developing prodromal symptoms of the disease and that these associations persist after accounting for the effects of other recognized behavioral and genetic markers of the disease.
In search of common risk alleles for prostate cancer that could contribute to high rates of the disease in men of African ancestry, we conducted a genome-wide association study (GWAS), with 1,047,986 single nucleotide polymorphism (SNP) markers examined in 3,425 African American prostate cancer cases and 3,290 African American male controls. The most significant 17 novel associations in stage 1 were followed-up in 1,844 cases and 3,269 controls of African ancestry. We identified a novel risk variant on chromosome 17q21 (rs7210100; odds ratio per allele=1.51; p=3.4×10−13). The frequency of the risk allele is ~5% in men of African descent while it is rare in other populations (<1%). Further studies are needed to investigate the biological contribution of this allele to prostate cancer risk. These findings emphasize the importance of conducting GWAS in diverse populations.
Neuroserpin, primarily localized to CNS neurons, inhibits the adverse effects of tissue-type plasminogen activator (tPA) on the neurovascular unit and has neuroprotective effects in animal models of ischemic stroke. We sought to evaluate the association of neuroserpin polymorphisms with risk for ischemic stroke among young women.
A population-based case-control study of stroke among women aged 15–49 identified 224 cases of first ischemic stroke (47.3% African-American) and 211 age-matched control subjects (43.1% African-American). Neuroserpin single nucleotide polymorphisms (SNPs) chosen through HapMap were genotyped in the study population and assessed for association with stroke.
Of the five SNPs analyzed, the A allele (frequency; Caucasian = 0.56, African-American = 0.42) of SNP rs6797312 located in intron 1 was associated with stroke in an age-adjusted dominant model (AA and AT vs. TT) among Caucasians (OR = 2.05, p = 0.023) but not African-Americans (OR = 0.71, p = 0.387). Models adjusting for other risk factors strengthened the association. Race-specific haplotype analyses, inclusive of SNP rs6797312, again demonstrated significant associations with stroke among Caucasians only.
This study provides the first evidence that neuroserpin is associated with early-onset ischemic stroke among Caucasian women.
Numerous single nucleotide polymorphisms (SNPs) within different genes have been associated with alcohol and drug involvement or known risk factors for involvement, such as impaired cognitive control. The ability of these SNPs to predict re-involvement, defined here as abstinence failure during treatment, has not been thoroughly tested.
We studied a small sample (n=146; 49% female) of residential substance abuse treatment program patients who had maintained 2–6 months of abstinence. They were followed for 4 months thereafter for the purpose of counting days until the first abstinence violation. The analysis used logistic and Cox regression methods to evaluate the contributions of age; sex; number of intake alcohol, drug use, and depression symptoms; and either GABRA2, CHRM2, ANKK1, BDNF, or KIBRA SNP genotypes to outcome.
GABRA2 and KIBRA genotypes, as well as the number of intake drug abuse problems and a younger age, were associated with an increased risk of relapse. Importantly, these genotypes were found to add value to relapse prediction: the χ2 statistic evaluating their residual contribution, after age and the number of previous drug use problems were entered, was significant.
Genetic analyses may add value to outcome prediction. Future studies should evaluate the sensitivity and specificity of GABRA2 and KIBRA genotypes for this purpose in other racial/ethnic groups and treatment settings.
GABRA2; KIBRA; CHRM2; ANKK1; BDNF; gene; relapse; substance use disorder; treatment outcome