Showing papers by "Alison Goate published in 2011"

Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease.

Abstract: We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ≤ 1 × 10−5. We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10−17; including ADGC data, meta P = 5.0 × 10−21) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10−14; including ADGC data, meta P = 1.2 × 10−16) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10−4; including ADGC data, meta P = 8.6 × 10−9), CD33 (GERAD+, P = 2.2 × 10−4; including ADGC data, meta P = 1.6 × 10−9) and EPHA1 (GERAD+, P = 3.4 × 10−4; including ADGC data, meta P = 6.0 × 10−10).

Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease.

Abstract: The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P(M)) = 1.7 × 10(-9), joint analysis P (P(J)) = 1.7 × 10(-9); stages 1, 2 and 3, P(M) = 8.2 × 10(-12)), CD2AP (rs9349407; stages 1, 2 and 3, P(M) = 8.6 × 10(-9)), EPHA1 (rs11767557; stages 1, 2 and 3, P(M) = 6.0 × 10(-10)) and CD33 (rs3865444; stages 1, 2 and 3, P(M) = 1.6 × 10(-9)). We also replicated previous associations at CR1 (rs6701713; P(M) = 4.6 × 10(-10), P(J) = 5.2 × 10(-11)), CLU (rs1532278; P(M) = 8.3 × 10(-8), P(J) = 1.9 × 10(-8)), BIN1 (rs7561528; P(M) = 4.0 × 10(-14), P(J) = 5.2 × 10(-14)) and PICALM (rs561655; P(M) = 7.0 × 10(-11), P(J) = 1.0 × 10(-10)), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility.

Alzheimer’s Disease: The Challenge of the Second Century

Abstract: Alzheimer’s disease (AD) was first described a little more than 100 years ago. It is the most common cause of dementia with an estimated prevalence of 30 million people worldwide, a number that is expected to quadruple in 40 years. There currently is no effective treatment that delays the onset or slows the progression of AD. However, major scientific advances in the areas of genetics, biochemistry, cell biology, and neuroscience over the past 25 years have changed the way we think about AD. This review discusses some of the challenges to translating these basic molecular and cellular discoveries into clinical therapies. Current information suggests that if the disease is detected before the onset of overt symptoms, it is possible that treatments based on knowledge of underlying pathogenesis can and will be effective.

Human apoE Isoforms Differentially Regulate Brain Amyloid-β Peptide Clearance

Abstract: The apolipoprotein E (APOE) e4 allele is the strongest genetic risk factor for late-onset, sporadic Alzheimer's disease (AD). The APOE e4 allele markedly increases AD risk and decreases age of onset, likely through its strong effect on the accumulation of amyloid-β (Aβ) peptide. In contrast, the APOE e2 allele appears to decrease AD risk. Most rare, early-onset forms of familial AD are caused by autosomal dominant mutations that often lead to overproduction of Aβ(42) peptide. However, the mechanism by which APOE alleles differentially modulate Aβ accumulation in sporadic, late-onset AD is less clear. In a cohort of cognitively normal individuals, we report that reliable molecular and neuroimaging biomarkers of cerebral Aβ deposition vary in an apoE isoform-dependent manner. We hypothesized that human apoE isoforms differentially affect Aβ clearance or synthesis in vivo, resulting in an apoE isoform-dependent pattern of Aβ accumulation later in life. Performing in vivo microdialysis in a mouse model of Aβ-amyloidosis expressing human apoE isoforms (PDAPP/TRE), we find that the concentration and clearance of soluble Aβ in the brain interstitial fluid depends on the isoform of apoE expressed. This pattern parallels the extent of Aβ deposition observed in aged PDAPP/TRE mice. ApoE isoform-dependent differences in soluble Aβ metabolism are observed not only in aged but also in young PDAPP/TRE mice well before the onset of Aβ deposition in amyloid plaques in the brain. Additionally, amyloidogenic processing of amyloid precursor protein and Aβ synthesis, as assessed by in vivo stable isotopic labeling kinetics, do not vary according to apoE isoform in young PDAPP/TRE mice. Our results suggest that APOE alleles contribute to AD risk by differentially regulating clearance of Aβ from the brain, suggesting that Aβ clearance pathways may be useful therapeutic targets for AD prevention.

Genome-Wide Association of Familial Late-Onset Alzheimer's Disease Replicates BIN1 and CLU and Nominates CUGBP2 in Interaction with APOE

Abstract: Late-onset Alzheimer’s disease (LOAD) is the most common form of dementia in the elderly. The National Institute of AgingLate Onset Alzheimer’s Disease Family Study and the National Cell Repository for Alzheimer’s Disease conducted a joint genome-wide association study (GWAS) of multiplex LOAD families (3,839 affected and unaffected individuals from 992 families plus additional unrelated neurologically evaluated normal subjects) using the 610 IlluminaQuad panel. This cohort represents the largest family-based GWAS of LOAD to date, with analyses limited here to the European-American subjects. SNPs near APOE gave highly significant results (e.g., rs2075650, p=3.2610 281 ), but no other genome-wide significant evidence for association was obtained in the full sample. Analyses that stratified on APOE genotypes identified SNPs on chromosome 10p14 in CUGBP2 with genome-wide significant evidence for association within APOE e4 homozygotes (e.g., rs201119, p=1.5610 28 ). Association in this gene was replicated in an independent sample consisting of three cohorts. There was evidence of association for recently-reported LOAD risk loci, including BIN1 (rs7561528, p=0.009 with, and p=0.03 without, APOE adjustment) and CLU (rs11136000, p=0.023 with, and p=0.008 without, APOE adjustment), with weaker support for CR1. However, our results provide strong evidence that association with PICALM (rs3851179, p=0.69 with, and p=0.039 without, APOE adjustment) and EXOC3L2 is affected by correlation with APOE, and thus may represent spurious association. Our results indicate that genetic structure coupled with ascertainment bias resulting from the strong APOE association affect genome-wide results and interpretation of some recently reported associations. We show that a locus such as APOE, with large effects and strong association with disease, can lead to samples that require appropriate adjustment for this locus to avoid both false positive and false negative evidence of association. We suggest that similar adjustments may also be needed for many other large multi-site studies.

A Quantitative-Trait Genome-Wide Association Study of Alcoholism Risk in the Community: Findings and

Abstract: Results: Nofindings reached genome-wide significance (p 8.4 10 8 for this study), with lowestp value for primary phenotypes of 1.2 10 7 . Convergent findings for quantitative consumption and diagnostic and quantitative dependence measures suggest possible roles for a transmembrane protein gene (TMEM108) and for ANKS1A. The major finding, however, was small effect sizes estimated for individual SNPs, suggesting that hundreds of genetic variants make modest contributions (1/4% of variance or less) to alcohol dependence risk. Conclusions: We conclude that 1) meta-analyses of consumption data may contribute usefully to gene discovery; 2) translation of human alcoholism GWAS results to drug discovery or clinically useful prediction of risk will be challenging; and 3) through accumulation across studies, GWAS data may become valuable for improved genetic risk differentiation in research in biological psychiatry (e.g., prospective high-risk or resilience studies).

Association of TMEM106B Gene Polymorphism With Age at Onset in Granulin Mutation Carriers and Plasma Granulin Protein Levels

Abstract: Objective—A recent genome-wide association study for frontotemporal lobar degeneration with TAR DNA-binding protein inclusions (FTLD-TDP), identified rs1990622 (TMEM106B) as a risk factor for FTLD-TDP. In this study we tested whether rs1990622 is associated with age at onset (AAO) in granulin (GRN) mutation carriers and with plasma GRN levels in mutation carriers and healthy elderly individuals. Design—Rs1990622 was genotyped in GRN mutation carriers and tested for association with AAO using the Kaplan-Meier and a Cox proportional hazards model. Subjects—We analyzed 50 affected and unaffected GRN mutation carriers from four previously reported FTLD-TDP families (HDDD1, FD1, HDDD2 and the Karolinska family). GRN plasma levels were also measured in 73 healthy, elderly individuals.

Amyloid-beta plaque growth in cognitively normal adults: longitudinal [11C]Pittsburgh compound B data.

Abstract: Amyloid-beta (Aβ) accumulation was evaluated with two PIB PET scans about 2.5 years apart in 146 cognitively normal adults. Seventeen of 21 participants with initially elevated Aβ deposition demonstrated subsequent Aβ plaque growth (approximately 8.0% per year) and none reverted to a state of no Aβ deposits. Ten individuals converted from negative to positive PIB status, based on a threshold of the mean cortical binding potential, representing a conversion rate of 3.1% per year. Individuals with an e4 allele of apolipoprotein E demonstrated increased incidence of conversion (7.0% per year). Our findings suggest that the major growth in Aβ burden occurs during a preclinical stage of AD, prior to the onset of AD-related symptoms.

Elevated Cortisol in Older Adults With Generalized Anxiety Disorder Is Reduced by Treatment: A Placebo-Controlled Evaluation of Escitalopram

Abstract: Background Generalized anxiety disorder (GAD) is a common disorder in older adults, which has been linked to hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis in this age group. The authors examined whether treatment of GAD in older adults with a selective serotonin reuptake inhibitor (SSRI) corrects this HPA axis hyperactivity. Methods The authors examined adults aged 60 years and older with GAD in a 12-week randomized controlled trial comparing the SSRI escitalopram with placebo. The authors collected salivary cortisol at six daily time points for 2 consecutive days to assess peak and total (area under the curve) cortisol, both at baseline and posttreatment. Results Compared with placebo-treated patients, SSRI-treated patients had a significantly greater reduction in both peak and total cortisol. This reduction in cortisol was limited to patients with elevated (above the median) baseline cortisol, in whom SSRI-treated patients showed substantially greater reduction in cortisol than did placebo-treated patients. Reductions in cortisol were associated with improvements in anxiety. Additionally, genetic variability at the serotonin transporter promoter predicted cortisol changes. Conclusions SSRI treatment of GAD in older adults reduces HPA axis hyperactivity. Further research should determine whether these treatment-attributable changes are sustained and beneficial.

Exome-Sequencing Confirms DNAJC5 Mutations as Cause of Adult Neuronal Ceroid-Lipofuscinosis

Abstract: We performed whole-exome sequencing in two autopsy-confirmed cases and an elderly unaffected control from a multigenerational family with autosomal dominant neuronal ceroid lipofuscinosis (ANCL). A novel single-nucleotide variation (c.344T>G) in the DNAJC5 gene was identified. Mutational screening in an independent family with autosomal dominant ANCL found an in-frame single codon deletion (c.346_348 delCTC) resulting in a deletion of p.Leu116del. These variants fulfill all genetic criteria for disease-causing mutations: they are found in unrelated families with the same disease, exhibit complete segregation between the mutation and the disease, and are absent in healthy controls. In addition, the associated amino acid substitutions are located in evolutionarily highly conserved residues and are predicted to functionally affect the encoded protein (CSPα). The mutations are located in a cysteine-string domain, which is required for membrane targeting/binding, palmitoylation, and oligomerization of CSPα. We performed a comprehensive in silico analysis of the functional and structural impact of both mutations on CSPα. We found that these mutations dramatically decrease the affinity of CSPα for the membrane. We did not identify any significant effect on palmitoylation status of CSPα. However, a reduction of CSPα membrane affinity may change its palmitoylation and affect proper intracellular sorting. We confirm that CSPα has a strong intrinsic aggregation propensity; however, it is not modified by the mutations. A complementary disease-network analysis suggests a potential interaction with other NCLs genes/pathways. This is the first replication study of the identification of DNAJC5 as the disease-causing gene for autosomal dominant ANCL. The identification of the novel gene in ANCL will allow us to gain a better understanding of the pathological mechanism of ANCLs and constitutes a great advance toward the development of new molecular diagnostic tests and may lead to the development of potential therapies.

Association and Expression Analyses With Single-Nucleotide Polymorphisms in TOMM40 in Alzheimer Disease

Abstract: Background Apolipoprotein E (APOE) is the most statistically significant genetic risk factor for late-onset Alzheimer disease (LOAD). The linkage disequilibrium pattern around the APOE gene has made it difficult to determine whether all the association signal is derived from APOE or whether there is an independent signal from a nearby gene. Objective To attempt to replicate a recently reported association of APOE 3–TOMM40 haplotypes with risk and age at onset. Design We used standard techniques to genotype several polymorphisms in the APOE–TOMM40 region in a large case-control series, in a series with cerebrospinal fluid biomarker data, and in brain tissue. Setting Alzheimer's Disease Research Center. Participants Research volunteers who were cognitively normal or had Alzheimer disease. Main Outcome Measures Disease status and age at onset. Results We did not replicate the previously reported association of the polyT polymorphism (rs10524523) with risk and age at onset. We found a significant association between rs10524523 and risk of LOAD in APOE 33 homozygotes but in the opposite direction as the previously reported association (the very long allele was underrepresented in cases vs controls in this study (P = .004]). We found no association between rs10524523 and cerebrospinal fluid tau or β-amyloid 42 levels or TOMM40 or APOE gene expression. Conclusions Although we did not replicate the earlier association between the APOE 3–TOMM40 haplotypes and age at onset, we observed that the polyT polymorphism is associated with risk of LOAD in APOE 33 homozygotes in a large case-control series but in the opposite direction as in the previous study.

The contribution of common CYP2A6 alleles to variation in nicotine metabolism among European-Americans.

Abstract: Cytochrome P450 2A6 (CYP2A6) is the primary catalyst of nicotine metabolism. To develop a predictive genetic model of nicotine metabolism, the conversion of deuterated (D2)-nicotine to D2-cotinine was quantified in 189 European Americans and the contribution of CYP2A6 genotype to variability in first-pass nicotine metabolism was assessed. Specifically, 1) single time-point measures of D2-cotinine/(D2-cotinine + D2-nicotine) following oral administration were used as a metric of CYP2A6 activity; 2) the impact of CYP2A6 haplotype was treated as acting multiplicatively; 3) parameter estimates were calculated for all haplotypes in the subject pool, defined by a set of polymorphisms previously reported to affect function, including gene copy number; and 4) a minimum number of predictive polymorphisms are justified to be included in the model based on statistical evidence of differences between haplotypes. The final model includes seven polymorphisms and fits the phenotype, 30 minutes following D2-nicotine oral administration, with R2=0.719. The predictive power of the model is robust: parameter estimates calculated in men (n=89) predict the phenotype in women (n=100) with R2=0.758 and vice versa with R2=0.617; estimates calculated in current smokers (n=102) predict phenotype in former smokers (n=86) with R2=0.690 and vice versa with R2=0.703. Comparisons of haplotypes also demonstrate that CYP2A6*12 is a loss of function allele indistinguishable from CYP2A6*4 and CYP2A6*2 and that the CYP2A6*1B 5′ UTR conversion has negligible impact on metabolism. After controlling for CYP2A6 genotype modest associations were found between increased metabolism and both female gender (p= 4.8×10−4) and current smoking (p=0.02).

A genome-wide association study of DSM-IV: Cannabis dependence

Abstract: Cannabis dependence is the third leading contributor to admissions to chemical dependency treatment settings (Treatment Episode Data Set, 2003) and rates of past year cannabis dependence in the U.S. population have increased by 18% since 1991–1992 (Compton et al., 2004). Several studies report strong heritable influences on cannabis dependence [h2 of 50–70%] (Agrawal and Lynskey, 2006). In an effort to identify contributors to this composite heritability, multiple linkage and association studies have been conducted. Several promising linkage regions (e.g. chromosome 3) exist. Candidate gene studies have largely focused on variants in the gene encoding the cannabinoid receptor CNR1 – results remain equivocal (Agrawal and Lynskey, 2009). To our knowledge, there are currently no published genomewide association studies (GWAS) of cannabis dependence. The goal of this investigation is to conduct association analysis between 948,142 single nucleotide polymorphisms (SNPs) and lifetime DSM-IV cannabis dependence using data on 708 cases with DSM-IV cannabis dependence and 2346 controls who report lifetime cannabis use but do not meet criteria for DSM-IV dependence. Data for this study come from the Study of Addiction: Genes and Environment (SAGE) (Bierut et al., 2010), which was one of the 8 Phase 1 studies of the Gene Environment Association (GENEVA) consortium (Cornelis et al., 2010). The study was designed primarily to study DSM-IV alcohol dependence as well as other correlated addiction phenotypes. All phenotypic data were collected using the Semi-Structured Assessment for the Genetics of Alcoholism Interview (SSAGA) (Bucholz et al., 1994b). Reliability of SSAGA diagnoses of substance use disorders is good (kappas of 0.7 and higher)(Bucholz et al., 1994a). Case status for the analyses reported here was defined as a lifetime history of DSM-IV cannabis dependence, modified to include cannabis withdrawal (i.e. 3 or more of 7 criteria clustering within a 12-month period). Controls had used cannabis at least once in their lifetime but did not meet criteria for DSM-IV dependence criteria (however, those meeting criteria for dependence on other psychoactive substances, including alcohol, were not excluded). Those who had never used cannabis even once in their lifetime (N=946) were omitted (however, re-doing analyses including them as unaffected showed similar results). DNA samples were genotyped on the Illumina Human 1M beadchip by the Center for Inherited Diseases Research (CIDR) at Johns Hopkins University. 948,658 SNPs passed data cleaning procedures – further within-sample filtering for autosomal and X-chromosome markers yielded 948,142 markers. HapMap genotyping controls, duplicates, related subjects, and outliers were removed from the sample set. Two thousand and nineteen subjects reported being European American and 1,035 reported being African American. Further details are available in a related publication (Bierut et al., 2010). Logistic regressions analyses were conducted in PLINK (Purcell et al., 2007), controlling for sex, age (defined, using quartiles, as 3 dummy measures representing 34 years or younger, 35–39 years, 40–44 years, with 45 years and older as the reference group), study source (see Bierut et al., 2010 for details) and two principal components (computed in EIGENSTRAT/EIGENSOFT, (Price et al., 2006)) indexing continuous variation in ethnicity. The overall genomic inflation factor was 1.014 after controlling for principal components representing ethnicity, suggesting minimal stratification effects. Genotypes (917,694 autosomal SNPs and 30,448 SNPs on the X-chromosome) were coded as 0, 1 or 2 copies of the reference allele so that risk associated with genotype was modified with each additional copy of the reference allele. DSM-IV cannabis dependent cases were significantly more likely to be males (68% vs. 43%) and were less likely to report completion of high school (18% vs 10% who did not complete). Consistent with ascertainment, cases were significantly more likely than controls to meet criteria for alcohol (94% vs 46%), nicotine (78% vs 46%) and cocaine (73% vs 21%) dependence, greater use of other illicit drugs (88% vs 47%) as well as report a younger age at initiation of cannabis use (14.5 vs 17.4 years) and more recent (44% vs 19% using in the past year) cannabis involvement. Thus, cases show marked phenotypic similarity to the highly heritable TypeII/B cluster of cannabis dependent subjects (Ehlers et al., 2009). The lowest p-values were obtained for polymorphisms on chromosome 17 (rs1019238 and rs1431318, p-values < E−7; rs8065311, p-value < E−6; rs9894332 and rs10521290, p-values < E−5). The top SNP lies in the ankyrin-repeat and fibronectin type III domain containing 1 (ANKFN1) gene, which was previously identified in a genomic study of general vulnerability to substance use disorders (Johnson et al., 2009). The genomic control p-value for rs1019238 was 7.3 × 10−7 suggesting adequate control for ethnic variation. The remaining SNPs (except rs10521290) are non-genic but are in strong LD (r2 of 0.75–0.88) with SNPs in ANKFN1. Fibronectin repeats are important constituents of a variety of proteins (Bloom and Calabro, 2009) and ankyrin repeats mediate protein interactions (Li et al., 2006). While there are links between ANKFN1 and PTEN (phosphatase and tensin homolog) in tumorigenesis (Syed et al., 2010), the specific role that ANKFN1 might play in the etiology of cannabis dependence is unknown. Table 1 presents odds-ratios for the full sample, as well as results stratified by ethnicity, for SNPs that yielded the most promising results. A number of genes on chromosome 12 (including the p- and q-arm) were associated, including carbohydrate (chondroitin 4) sulfotransferase 11 (CHST11). None of the SNPs that emerged as our top findings have known functional significance. Association results across the full autosomal genome and the X chromosome are shown in Figure 1. Figure 1 Manhattan plot showing genomewide association results for autosomal SNPs and SNPs on the X chromosome for DSM-IV cannabis dependence in SAGE. Table 1 Association results of top 30 SNPs from a genomewide association study of 708 DSM-IV cannabis dependence cases and 2346 controls from SAGE. (All allele frequencies and odds-ratios reflect analysis of increasing risk associated with the reference allele). ... While our primary analyses accounted for population stratification, we also show, in Table 1, findings within each ethnic group. A number of the SNPs showed ethnic variations in allele frequency. In a majority of instances, odds-ratios were comparable across the European- and African-American samples. However, 5 SNPs were found to have exceedingly low MAFs in the European-American sample suggesting that their overall significance in the full sample may be attributable to their effects in the smaller African-American sample. A limitation of this study is that SAGE was ascertained for alcohol dependence. This led to a high level of comorbidity in the cannabis dependent cases and exposed controls. However, the use of controls with other forms of substance dependence, but not cannabis dependence, protected against signals that may have been less specific. In addition, a series of analyses was conducted that supported the specificity of these findings. First, SNPs in ANKFN1 were not significant when case status was alcohol (also nicotine and cocaine) dependence without comorbid cannabis dependence. Second, we created a polydrug dependence diagnosis, and results were not significant when cannabis dependent individuals were excluded from those with other polydrug dependence. While a sample ascertained for cannabis dependence would be ideal, there are challenges associated with the recruitment of such a sample (Agrawal and Lynskey, 2009), and to our knowledge, no such samples currently exist. Further, while cannabis dependence is highly heritable, none of our association signals reach genomewide significance, nor do the composite of the top 30 signals explain a considerable proportion of this heritable variance in cannabis dependence. The Benjamini-Hochberg False Discovery Rate (Benjamini and Hochberg, 1995) for the top signal was .325. Power computations reveal that at MAFs ranging from 15–40%, association signals with odds-ratios exceeding 1.45, such as our top SNP, would be detected. Thus, both replication and meta-analysis are required to confirm or refute these findings. Characterizing the genetic underpinnings of cannabis dependence remains elusive – to this end, results from GWAS might provide clues into alternative biological pathways that shape the etiology of cannabis dependence.

Genome-Wide Association Study of Theta Band Event-Related Oscillations Identifies Serotonin Receptor Gene HTR7 Influencing Risk of Alcohol Dependence

Abstract: Event-related brain oscillations (EROs) represent highly heritable neuroelectrical correlates of human perception and cognitive performance that exhibit marked deficits in patients with various psychiatric disorders. We report the results of the first genome-wide association study (GWAS) of an ERO endophenotype—frontal theta ERO evoked by visual oddball targets during P300 response in 1,064 unrelated individuals drawn from a study of alcohol dependence. Forty-two SNPs of the Illumina HumanHap 1 M microarray were selected from the theta ERO GWAS for replication in family-based samples (N = 1,095), with four markers revealing nominally significant association. The most significant marker from the two-stage study is rs4907240 located within ARID protein 5A gene (ARID5A) on chromosome 2q11 (unadjusted, Fisher's combined P = 3.68 × 10−6). However, the most intriguing association to emerge is with rs7916403 in serotonin receptor gene HTR7 on chromosome 10q23 (combined P = 1.53 × 10−4), implicating the serotonergic system in the neurophysiological underpinnings of theta EROs. Moreover, promising SNPs were tested for association with diagnoses of alcohol dependence (DSM-IV), revealing a significant relationship with the HTR7 polymorphism among GWAS case–controls (P = 0.008). Significant recessive genetic effects were also detected for alcohol dependence in both case–control and family-based samples (P = 0.031 and 0.042, respectively), with the HTR7 risk allele corresponding to theta ERO reductions among homozygotes. These results suggest a role of the serotonergic system in the biological basis of alcohol dependence and underscore the utility of analyzing brain oscillations as a powerful approach to understanding complex genetic psychiatric disorders. © 2010 Wiley-Liss, Inc.

Mapping the Road Forward in Alzheimer’s Disease

Abstract: Alzheimer’s disease (AD) is the most common cause of dementia and will lead to a worldwide public health crisis if it continues unchecked. Despite tremendous advances in our scientific understanding of AD, we still do not have effective ways to delay, prevent, or slow this disease. At the 2011 Abelson meeting, a diverse group of scientists discussed current challenges in the AD field and made recommendations in the areas of genetics, clinical trials, protein aggregation, and the cell biology of the nervous system. We hope these recommendations will boost research progress in AD and increase the likelihood of developing effective therapies in the near future.

Fine Mapping of Genetic Variants in BIN1, CLU, CR1 and PICALM for Association with Cerebrospinal Fluid Biomarkers for Alzheimer's Disease

Abstract: Recent genome-wide association studies of Alzheimer's disease (AD) have identified variants in BIN1, CLU, CR1 and PICALM that show replicable association with risk for disease. We have thoroughly sampled common variation in these genes, genotyping 355 variants in over 600 individuals for whom measurements of two AD biomarkers, cerebrospinal fluid (CSF) 42 amino acid amyloid beta fragments (Aβ42) and tau phosphorylated at threonine 181 (ptau181), have been obtained. Association analyses were performed to determine whether variants in BIN1, CLU, CR1 or PICALM are associated with changes in the CSF levels of these biomarkers. Despite adequate power to detect effects as small as a 1.05 fold difference, we have failed to detect evidence for association between SNPs in these genes and CSF Aβ42 or ptau181 levels in our sample. Our results suggest that these variants do not affect risk via a mechanism that results in a strong additive effect on CSF levels of Aβ42 or ptau181.

CHRM2, Parental Monitoring, and Adolescent Externalizing Behavior Evidence for Gene-Environment Interaction

Abstract: Psychologists, with their long-standing tradition of studying mechanistic processes, can make important contributions to further characterizing the risk associated with genes identified as influencing risk for psychiatric disorders. We report one such effort with respect to CHRM2, which codes for the cholinergic muscarinic 2 receptor and was of interest originally for its association with alcohol dependence. We tested for association between CHRM2 and prospectively measured externalizing behavior in a longitudinal, community-based sample of adolescents, as well as for moderation of this association by parental monitoring. We found evidence for an interaction in which the association between the genotype and externalizing behavior was stronger in environments with lower parental monitoring. There was also suggestion of a crossover effect, in which the genotype associated with the highest levels of externalizing behavior under low parental monitoring had the lowest levels of externalizing behavior at the extreme high end of parental monitoring. The difficulties involved in distinguishing mechanisms of gene-environment interaction are discussed.

Differential susceptibility to adolescent externalizing trajectories: examining the interplay between CHRM2 and peer group antisocial behavior.

Abstract: The present study characterized prototypical patterns of development in self-reported externalizing behavior, between 12 and 22 years of age, within a community sample of 452 genotyped individuals. A Caucasian subset (n = 378) was then examined to determine whether their probabilities of displaying discrete trajectories were differentially associated with CHRM2, a gene implicated in self-regulatory processes across a range of externalizing behaviors, and if affiliating with antisocial peers moderated these associations. Findings indicate that relative to a normative “lower risk” externalizing trajectory, likelihood of membership in two “higher risk” trajectories increased with each additional copy of the minor allelic variant at CHRM2, and that this association was exacerbated among those exposed to higher levels of peer group antisocial behavior.

A 3p26-3p25 Genetic Linkage Finding for DSM-IV Major Depression in Heavy Smoking Families

Abstract: Objective:The authors tested for genetic linkage of DSM-IV-diagnosed major depressive disorder in families that were ascertained for cigarette smoking. Method:Within a study that targeted families characterized by a history of smoking, analyses derived a subset of 91 Australian families with two or more offspring with a history of DSM-IV major depressive disorder (affected sibling pairs, N=187) and 25 Finnish families (affected sibling pairs, N=33). Within this affected sibling pairs design, the authors conducted nonparametric linkage analysis. Results:In the Australian heavy smoking families, the authors found a genome-wide significant multipoint LOD score of 4.14 for major depressive disorder on chromosome 3 at 24.9 cM (3p26-3p25). Conclusions:Genome-wide significant linkage was detected for major depressive disorder on chromosome 3p in a sample ascertained for smoking. A linkage peak at this location was also observed in an independent study of major depressive disorder.

Dissection of the phenotypic and genotypic associations with nicotinic dependence

Abstract: Introduction: Strong evidence demonstrates that nicotine dependence is associated with 4 genetic variants rs16969968, rs6474412, rs3733829, and rs1329650 in large-scale Genome-Wide Association Studies. We examined how these identified genetic variants relate to nicotine dependence defined by different categorical and dimensional measures.

Alternative processing of γ-secretase substrates in common forms of mild cognitive impairment and Alzheimer's disease: evidence for γ-secretase dysfunction.

Abstract: The most common pathogenesis for familial Alzheimer's disease (FAD) involves misprocessing/alternative processing of the amyloid precursor protein (APP) by γ-secretase (for review, see Gandy1 and Small and Gandy2). This misprocessing/alternative processing leads to a relative increase in the ratio of the level of a minor γ-secretase reaction product, amyloid-β42 (Aβ42), to that of the major reaction product, amyloid-β40 (Aβ40; Borchelt and colleagues3). Until now, little has been known about γ-secretase function in sporadic AD (SAD). We approached this issue by studying the metabolite peptides, p3-Alcα, that are derived from the processing by α-secretases and γ-secretases of the alcadeinα (Alcα), member of the alcadein (Alc) protein family. Alc proteins colocalize with APP in healthy mouse and SAD human brain,4 but they are entirely distinct from APP in their polypeptide sequence. In neurons, Alc proteins are complexed to APP via X11L adaptor molecules, raising the possibility that Alcs might be sorted and processed together with APP. Experimental evidence supports this reasoning. In the absence of X11L, both Alc and APP proteins are rapidly metabolized by proteolysis.5 Levels of the endogenous APP metabolite, Aβ, are elevated in the brains of X11L-deficient mice.6,7 Thus, taken together with similarities in their structure and cellular distribution, APP and Alc proteins would be predicted to undergo parallel metabolic fates (for APP and X11L, see Gandy1 and Suzuki and Nakaya8; for Alc, see Araki and colleagues,4,5,9). Alc proteins exist in mammalian neurons as 4 isoforms4: Alcα1, Alcα2, Alcβ, and Alcγ. Alcα, Alcβ, and Alcγ are encoded by independent genes, while Alcα1 and Alcα2 are splice variants derived from the Alcα gene. All 3 members of the Alc family (Alcα, Alcβ, and Alcγ) are cleaved by ADAM 10 and ADAM 17, which have been identified as the α-secretases for APP.10–13 Subsequent cleavage of the remaining Alc C-terminal fragments involves predominantly the presenilin 1-(PS1)-dependent γ-secretase, and this reaction liberates a short peptide that we have designated p3-Alcα into cell-conditioned media and into cerebrospinal fluid (CSF). The amino acid sequences of the various alternatively cleaved p3-Alcα peptides in human CSF are shown with those of APP-p3 and Aβ (Fig 1). The current study is based on the hypothesis that examination of AD-related processing of p3-Alcα might reveal evidence for γ-secretase dysfunction in SAD. In so doing, we seek to confirm and extend the report of Yanagida and colleagues,14 who described similar alternative processing of another γ-secretase substrate, APLP. Taken together with the data from Yanagida and colleagues,14 we suggest that multiple γ-secretase substrates are subjected to altered processing in SAD and that this potentially implicates an “acquired” γ-secretase dysfunction that might contribute the pathogenesis of SAD. Figure 1 Amino acid sequences and cleavage sites of p3-Alcα and Aβ in human CSF. The amino acid sequences of p3-Alcα (black-underline) along with the sequences of p3 (gray double-underline) and Aβ40 (black double-underline) of APP. ...

FUS Immunogold Labeling TEM Analysis of the Neuronal Cytoplasmic Inclusions of Neuronal Intermediate Filament Inclusion Disease: A Frontotemporal Lobar Degeneration with FUS Proteinopathy

Abstract: Fused in sarcoma (FUS)-immunoreactive neuronal and glial inclusions define a novel molecular pathology called FUS proteinopathy. FUS has been shown to be a component of inclusions of familial amyotrophic lateral sclerosis with FUS mutation and three frontotemporal lobar degeneration entities, including neuronal intermediate filament inclusion disease (NIFID). The pathogenic role of FUS is unknown. In addition to FUS, many neuronal cytoplasmic inclusions (NCI) of NIFID contain aggregates of -internexin and neurofilament proteins. Herein, we have shown that: (1) FUS becomes relatively insoluble in NIFID and there are no apparent posttranslational modifications, (2) there are no pathogenic abnormalities in the FUS gene in NIFID, and (3) immunoelectron microscopy demonstrates the fine structural localization of FUS in NIFID which has not previously been described. FUS localized to euchromatin, and strongly with paraspeckles, in nuclei, consistent with its RNA/DNA-binding functions. NCI of varying morphologies were observed. Most frequent were the "loosely aggregated cytoplasmic inclusions," 81% of which had moderate or high levels of FUS immunoreactivity. Much rarer "compact cytoplasmic inclusions" and "tangled twine ball inclusions" were FUS-immunoreactive at their granular peripheries, or heavily FUS-positive throughout, respectively. Thus, FUS may aggregate in the cytoplasm and then admix with neuronal intermediate filament accumulations.

Common polymorphisms in FMO1 are associated with nicotine dependence

Abstract: BACKGROUND Cigarette smoking and other forms of tobacco use are the leading cause of preventable mortality in the world A better understanding of the etiology of nicotine addiction may help increase the success rate of cessation and decrease the massive morbidity and mortality associated with smoking

Copy Number Variation Accuracy in Genome-Wide Association Studies

Abstract: Background/Aim: Copy number variations (CNVs) are a major source of alterations among individuals and are a potential risk factor in many diseases. Numerous diseases have been linked to deletions and duplications of these chromosomal segments. Data from genome-wide association studies and other microarrays may be used to identify CNVs by several different computer programs, but the reliability of the results has been questioned. Methods: To help researchers reduce the number of false-positive CNVs that need to be followed up with laboratory testing, we evaluated the relative performance of CNVPartition, PennCNV and QuantiSNP, and developed a statistical method for estimating sensitivity and positive predictive values of CNV calls and tested it on 96 duplicate samples in our dataset. Results: We found that the positive predictive rate increases with the number of probes in the CNV and the size of the CNV, with the highest positive predicted rates in CNVs of at least 500 kb and at least 100 probes. Our analysis also indicates that identifying CNVs reported by multiple programs can greatly improve the reproducibility rate and the positive predicted rate. Conclusion: Our methods can be used by investigators to identify CNVs in genome-wide data with greater reliability.

Uncovering hidden variance: pair-wise SNP analysis accounts for additional variance in nicotine dependence

Abstract: Results from genome-wide association studies of complex traits account for only a modest proportion of the trait variance predicted to be due to genetics. We hypothesize that joint analysis of polymorphisms may account for more variance. We evaluated this hypothesis on a case–control smoking phenotype by examining pairs of nicotinic receptor single-nucleotide polymorphisms (SNPs) using the Restricted Partition Method (RPM) on data from the Collaborative Genetic Study of Nicotine Dependence (COGEND). We found evidence of joint effects that increase explained variance. Four signals identified in COGEND were testable in independent American Cancer Society (ACS) data, and three of the four signals replicated. Our results highlight two important lessons: joint effects that increase the explained variance are not limited to loci displaying substantial main effects, and joint effects need not display a significant interaction term in a logistic regression model. These results suggest that the joint analyses of variants may indeed account for part of the genetic variance left unexplained by single SNP analyses. Methodologies that limit analyses of joint effects to variants that demonstrate association in single SNP analyses, or require a significant interaction term, will likely miss important joint effects.

Association and expression analyses with SNPs in TOMM40 in Alzheimer's disease

Abstract: St ephanie Debette, Helena Schmidt, James Wilson, Velandai Srikanth, Lina Zgaga, Mirna Kirin, Lei Yu, Jim Stankovich, Qiong Yang, Reinhold Schmidt, Caroline Hayward, Harry Campbell, Jan Bressler, Gail Davies, Josh Bis, Katja Petrovic, David Bennett, Sudha Seshadri, Albert Smith, Carla Ibrahim-Verbaas, Thomas Mosley, Mohammad Ikram, Maaike Schuur, Cornelia van Duijn, Monique Breteler, Ian Deary, Lenore Launer, Annette Fitzpatrick, Department of Neurology, Boston University School of Medicine, Boston, USA; 2 Department of Neurology, Medical University of Graz; Centre for Population Health Sciences, University of Edinburgh, Edinburgh; Stroke and Ageing Research Group, Neurosciences, Dept of Medicine, Southern Clinical School, Clayton, Victoria; 5 Public Health Sciences, University of Edinburgh, Edinburgh; 6 Centre for Population Health Sciences, University of Edinburgh, Edinburgh; Rush Alzheimer’s Disease Center, Rush University Medical Center, chicago, Illinois; The Menzies Research Institute, Hobart, Australia; 9 Boston University School of Medicine, Boston, Massachusetts; 10 Department of Neurology, Medical University of Graz, Graz; Public Health Sciences, University of Edinburgh, Edinburgh, United Kingdom; Centre for Population Health Sciences, University of Edinburgh, Edinburgh, United Kingdom; 13 Human Genetics Center RAS E-503, Houston, Texas; Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom; Department of Medicine, University of Washington, Seattle, Washington; 16 Department of Neurology, Medical University of Graz; 17 Department of Neurology, Boston University School of Medicine, the Framingham Heart Study, Boston, Massachusetts; AGES Reykjavik Icelandic Heart Association, Kopavogur, Iceland; 19 Erasmus University Medical Center, Rotterdam, The Netherlands; 20 Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi; Erasmus University Medical Center, Rotterdam, the Netherlands; Erasmus University Medical Center, Rotterdam; 23 Dept of Epidemiology, Erasmus MC, University Medical Center, Rotterdam; University of Edinburgh; Intramural Research Program, National Institute on Aging, Bethesda, Maryland; University of Washington, Seattle, Washington.