Cerebrospinal fluid APOE levels: an endophenotype for genetic studies for Alzheimer's disease.

The apolipoprotein E (APOE) genotype is the major genetic risk factor for Alzheimer's disease (AD). We have access to cerebrospinal fluid (CSF) and plasma APOE protein levels from 641 individuals and genome-wide genotyped data from 570 of these samples. The aim of this study was to test whether CSF or plasma APOE levels could be a useful endophenotype for AD and to identify genetic variants associated with APOE levels. We found that CSF (P = 8.15 × 10(-4)) but not plasma (P = 0.071) APOE protein levels are significantly associated with CSF Aß(42) levels. We used Mendelian randomization and genetic variants as instrumental variables to confirm that the association of CSF APOE with CSF Aß(42) levels and clinical dementia rating (CDR) is not because of a reverse causation or confounding effect. In addition the association of CSF APOE with Aß(42) levels was independent of the APOE ε4 genotype, suggesting that APOE levels in CSF may be a useful endophenotype for AD. We performed a genome-wide association study to identify genetic variants associated with CSF APOE levels: the APOE ε4 genotype was the strongest single-genetic factor associated with CSF APOE protein levels (P = 6.9 × 10(-13)). In aggregate, the Illumina chip single nucleotide polymorphisms explain 72% of the variability in CSF APOE protein levels, whereas the APOE ε4 genotype alone explains 8% of the variability. No other genetic variant reached the genome-wide significance threshold, but nine additional variants exhibited a P-value <10(-6). Pathway mining analysis indicated that these nine additional loci are involved in lipid metabolism (P = 4.49 × 10(-9)).

A meta-analysis of two genome-wide association studies to identify novel loci for maximum number of alcoholic drinks.

Maximum number of alcoholic drinks consumed in a 24-h period (maxdrinks) is a heritable (>50 %) trait and is strongly correlated with vulnerability to excessive alcohol consumption and subsequent alcohol dependence (AD). Several genome-wide association studies (GWAS) have studied alcohol dependence, but few have concentrated on excessive alcohol consumption. We performed two GWAS using maxdrinks as an excessive alcohol consumption phenotype: one in 118 extended families (N = 2,322) selected from the Collaborative Study on the Genetics of Alcoholism (COGA), and the other in a case-control sample (N = 2,593) derived from the Study of Addiction: Genes and Environment (SAGE). The strongest association in the COGA families was detected with rs9523562 (p = 2.1 × 10(-6)) located in an intergenic region on chromosome 13q31.1; the strongest association in the SAGE dataset was with rs67666182 (p = 7.1 × 10(-7)), located in an intergenic region on chromosome 8. We also performed a meta-analysis with these two GWAS and demonstrated evidence of association in both datasets for the LMO1 (p = 7.2 × 10(-7)) and PLCL1 genes (p = 4.1 × 10(-6)) with maxdrinks. A variant in AUTS2 and variants in INADL, C15orf32 and HIP1 that were associated with measures of alcohol consumption in a meta-analysis of GWAS studies and a GWAS of alcohol consumption factor score also showed nominal association in the current meta-analysis. The present study has identified several loci that warrant further examination in independent samples. Among the top SNPs in each of the dataset (p ≤ 10(-4)) far more showed the same direction of effect in the other dataset than would be expected by chance (p = 2 × 10(-3), 3 × 10(-6)), suggesting that there are true signals among these top SNPs, even though no SNP reached genome-wide levels of significance.

Escitalopram reduces attentional performance in anxious older adults with high-expression genetic variants at serotonin 2A and 1B receptors.

Older adults are among the most vulnerable to adverse cognitive effects of psychotropic medications and, therefore, the personalization of psychotropic treatment based on adverse drug reactions in this demographic is of great importance. We examined changes on neuropsychological tests of attention attributable to selective serotonin reuptake inhibitor (SSRI) treatment in anxious older adults. We also examined whether variation in serotonin receptor genes was associated with reduced attentional performance with SSRIs. We examined change from pre- to post-treatment in two attention measures - digit span and coding - in 133 adults aged ≥60 yr with generalized anxiety disorder in a 12-wk trial of escitalopram vs. placebo. We also examined attentional change in relation to genetic variability in four central serotonin receptors: the serotonin transporter and serotonin 1A, 2A and 1B receptors. Digit span scores were significantly lowered in patients receiving escitalopram relative to placebo, indicating reduced attentional performance attributable to the SSRI. Individuals with high-transcription variants in the receptors 5-HTR2A rs6311 and 5-HTR1B rs11568817 had greater reductions in attention with SSRI treatment compared to placebo. We conclude that SSRIs reduce attention in older adults, particularly in those with high-expression genetic variants at the serotonin 2A and 1B receptors. Analysing neuropsychological changes with SSRIs in relation to genetic variation in the serotonin system may be a useful strategy for detecting subgroups of older adults who are more susceptible to side-effects of SSRIs. These results, if confirmed, could lead to the personalization of SSRI use to reduce adverse neurocognitive effects.

A genome-wide association study of alcohol dependence.

Excessive alcohol consumption is one of the leading causes of preventable death in the United States. Approximately 14% of those who use alcohol meet criteria during their lifetime for alcohol dependence, which is characterized by tolerance, withdrawal, inability to stop drinking, and continued drinking despite serious psychological or physiological problems. We explored genetic influences on alcohol dependence among 1,897 European-American and African-American subjects with alcohol dependence compared with 1,932 unrelated, alcohol-exposed, nondependent controls. Constitutional DNA of each subject was genotyped using the Illumina 1M beadchip. Fifteen SNPs yielded P < 10(-5), but in two independent replication series, no SNP passed a replication threshold of P < 0.05. Candidate gene GABRA2, which encodes the GABA receptor alpha2 subunit, was evaluated independently. Five SNPs at GABRA2 yielded nominal (uncorrected) P < 0.05, with odds ratios between 1.11 and 1.16. Further dissection of the alcoholism phenotype, to disentangle the influence of comorbid substance-use disorders, will be a next step in identifying genetic variants associated with alcohol dependence.

Incorporating linkage information into a common disease/rare variant framework.

Recent developments in sequencing technology have allowed the investigation of the common disease/rare variant hypothesis. In the Genetic Analysis Workshop 17 data set, we have sequence data on both unrelated individuals and eight large extended pedigrees with simulated quantitative and qualitative phenotypes. Group 11, whose focus was incorporating linkage information, considered several different ways to use the extended pedigrees to identify causal genes and variants. The first issue was the use of standard linkage or identity-by-descent information to identify regions containing causal rare variants. We found that rare variants of large effect segregating through pedigrees were precisely the bailiwick of linkage analysis. For a common disease, we anticipate many risk loci, so a heterogeneity linkage analysis or an analysis of a single pedigree at a time may be useful. The second issue was using pedigree data to identify individuals for sequencing. If one can identify linked regions and even carriers of risk haplotypes, the sequencing will be substantially more efficient. In fact, sequencing only 2.5% of the genome in carefully selected individuals can detect 52% of the risk variants that would be detected through whole-exome sequencing in a large number of unrelated individuals. Finally, we found that linkage information from pedigrees can provide weights for case-control association tests. We also found that pedigree-based association tests have the same issues of binning variants and variant counting as those in tests of unrelated individuals. Clearly, when pedigrees are available, they can provide great assistance in the search for rare variants that influence common disorders.

Common polymorphisms in FMO1 are associated with nicotine dependence.

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 to increase the success rate of cessation and to decrease the massive morbidity and mortality associated with smoking. METHODS: To identify genetic polymorphisms that contribute to nicotine dependence, our group undertook a genetic association study including three enzyme families that potentially influence nicotine metabolism: cytochrome P450 enzymes, flavin monooxygenases (FMOs), and UDP-glucuronosyl transferases. RESULTS: Several polymorphisms in FMO1 showed association in a discovery sample, and were tested in an independent replication sample. One polymorphism, rs10912765, showed an association that remained significant after Bonferroni correction (nominal P=0.0067, corrected P=0.0134). Several additional polymorphisms in linkage disequilibrium with this single nucleotide polymorphism also showed association. Subsequent in-vitro experiments characterized FMO1 as a more efficient catalyst of nicotine N-oxidation than FMO3. In adult humans, FMO1 is primarily expressed in the kidney and is likely to be a major contributor to the renal metabolism and clearance of therapeutic drugs. FMO1 is also expressed in the brain and could contribute to the nicotine concentration in this tissue. CONCLUSION: These findings suggest that polymorphisms in FMO1 are significant risk factors in the development of nicotine dependence and that the mechanism may involve variation in nicotine pharmacology.

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

OBJECTIVE: To study the association between cytochrome P450 2A6 (CYP2A6) genotype and metabolism of nicotine to cotinine, identify functional polymorphisms, and develop a predictive genetic model of nicotine metabolism. METHODS: 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, (i) single time point measures of D2-cotinine/(D2-cotinine+D2-nicotine) after oral administration were used as a metric of CYP2A6 activity; (ii) the impact of CYP2A6 haplotype was treated as acting multiplicatively; (iii) 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 (iv) a minimum number of predictive polymorphisms were justified to be included in the model based on statistical evidence of differences between haplotypes. RESULTS: The final model includes seven polymorphisms and fits the phenotype, 30-min after D2-nicotine oral administration, with R=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 R=0.758 and vice versa with R=0.617; estimates calculated in current smokers (n=102) predict the phenotype in former-smokers (n=86) with R=0.690 and vice versa with R=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'-untranslated region conversion has negligible impact on metabolism. After controlling for CYP2A6 genotype, modest associations were found between increased metabolism and both female sex (P=4.8×10) and current smoking (P=0.02). CONCLUSION: Among European-Americans, seven polymorphisms in the CYP2A6 gene explain the majority of variability in the metabolism of nicotine to cotinine after oral administration. Parameters determined from this in-vivo experiment can be used to predict nicotine metabolism based on CYP2A6 genotype.

A genome-wide association study of DSM-IV cannabis dependence.

Despite twin studies showing that 50-70% of variation in DSM-IV cannabis dependence is attributable to heritable influences, little is known of specific genotypes that influence vulnerability to cannabis dependence. We conducted a genome-wide association study of DSM-IV cannabis dependence. Association analyses of 708 DSM-IV cannabis-dependent cases with 2346 cannabis-exposed non-dependent controls was conducted using logistic regression in PLINK. None of the 948 142 single nucleotide polymorphisms met genome-wide significance (P at E-8). The lowest P values were obtained for polymorphisms on chromosome 17 (rs1019238 and rs1431318, P values at E-7) in the ANKFN1 gene. While replication is required, this study represents an important first step toward clarifying the biological underpinnings of cannabis dependence.

Population stratification and patterns of linkage disequilibrium.

Although the importance of selecting cases and controls from the same population has been recognized for decades, the recent advent of genome-wide association studies has heightened awareness of this issue. Because these studies typically deal with large samples, small differences in allele frequencies between cases and controls can easily reach statistical significance. When, unbeknownst to a researcher, cases and controls have different substructures, the number of false-positive findings is inflated. There have been three recent developments of purely statistical approaches to assessing the ancestral comparability of case and control samples: genomic control, structured association, and multivariate reduction analyses. The widespread use of high-throughput technology has allowed the quick and accurate genotyping of the large number of markers required by these methods. Group 13 dealt with four population stratification issues: single-nucleotide polymorphism marker selection, association testing, nonstandard methods, and linkage disequilibrium calculations in stratified or mixed ethnicity samples. We demonstrated that there are continuous axes of ethnic variation in both data sets of Genetic Analysis Workshop 16. Furthermore, ignoring this structure created P-value inflation for a variety of phenotypes. Principal-components analysis (or multidimensional scaling) can control inflation as covariates in a logistic regression. One can weigh for local ancestry estimation and allow the use of related individuals. Problems arise in the presence of extremely high association or unusually strong linkage disequilibrium (e.g., in chromosomal inversions). Our group also reported a method for performing an association test controlling for substructure, when genome-wide markers are not available, to explicitly compute stratification.

Genome-wide association study of alcohol dependence implicates a region on chromosome 11.

BACKGROUND: Alcohol dependence is a complex disease, and although linkage and candidate gene studies have identified several genes associated with the risk for alcoholism, these explain only a portion of the risk. METHODS: We carried out a genome-wide association study (GWAS) on a case-control sample drawn from the families in the Collaborative Study on the Genetics of Alcoholism. The cases all met diagnostic criteria for alcohol dependence according to the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition; controls all consumed alcohol but were not dependent on alcohol or illicit drugs. To prioritize among the strongest candidates, we genotyped most of the top 199 single nucleotide polymorphisms (SNPs) (p < or = 2.1 x 10(-4)) in a sample of alcohol-dependent families and performed pedigree-based association analysis. We also examined whether the genes harboring the top SNPs were expressed in human brain or were differentially expressed in the presence of ethanol in lymphoblastoid cells. RESULTS: Although no single SNP met genome-wide criteria for significance, there were several clusters of SNPs that provided mutual support. Combining evidence from the case-control study, the follow-up in families, and gene expression provided strongest support for the association of a cluster of genes on chromosome 11 (SLC22A18, PHLDA2, NAP1L4, SNORA54, CARS, and OSBPL5) with alcohol dependence. Several SNPs nominated as candidates in earlier GWAS studies replicated in ours, including CPE, DNASE2B, SLC10A2, ARL6IP5, ID4, GATA4, SYNE1, and ADCY3. CONCLUSIONS: We have identified several promising associations that warrant further examination in independent samples.

Cortical atrophy and language network reorganization associated with a novel progranulin mutation.

Progressive nonfluent aphasia (PNFA) is an early stage of frontotemporal degeneration. We identified a novel Cys521Tyr progranulin gene variant in a PNFA family that potentially disrupts disulphide bridging causing protein misfolding. To identify early neurodegeneration changes, we performed neuropsychological and neuroimaging studies in 6 family members (MRI [magnetic resonance imaging], fMRI [functional MRI], and 18f-fluorodeoxygenlucose positron emission tomography, including 4 mutation carriers, and in 9 unrelated controls. Voxel-based morphometry (VBM) of the carriers compared with controls showed significant cortical atrophy in language areas. Grey matter loss was distributed mainly in frontal lobes, being more prominent on the left. Clusters were located in the superior frontal gyri, left inferior frontal gyrus, left middle frontal gyrus, left middle temporal gyri and left posterior parietal areas, concordant with (18)FDG-PET hypometabolic areas. fMRI during semantic and phonemic covert word generation (CWGTs) and word listening tasks (WLTs) showed recruitment of attentional and working memory networks in the carriers indicative of functional reorganization. During CWGTs, activation in left prefrontal cortex and bilateral anterior insulae was present whereas WLT recruited mesial prefrontal and anterior temporal cortex. These findings suggest that Cys521Tyr could be associated with early brain impairment not limited to language areas and compensated by recruitment of bilateral auxiliary cortical areas.

Evidence for association between polymorphisms in the cannabinoid receptor 1 (CNR1) gene and cannabis dependence.

Genomic studies of cannabis use disorders have been limited. The cannabinoid receptor 1 gene (CNR1) on chromosome 6q14-15 is an excellent candidate gene for cannabis dependence due to the important role of the G-protein coupled receptor encoded by this gene in the rewarding effects of Delta9-tetrahydrocannabinol. Previous studies have found equivocal evidence for an association between SNPs in CNR1 and a general vulnerability to substance use disorders. We investigate the association between 9 SNPs spanning CNR1 and cannabis dependence in 1,923 individuals. Two SNPs that were previously associated with cannabis dependence in other studies were also significant with this phenotype in our analyses [rs806368 (P = 0.05) and rs806380 (P = 0.009)]. Haplotype analyses revealed the association to be largely driven by the SNP rs806380. These results suggest a role for the cannabinoid receptor 1 gene in cannabis dependence.

Multiple distinct risk loci for nicotine dependence identified by dense coverage of the complete family of nicotinic receptor subunit (CHRN) genes.

Tobacco smoking continues to be a leading cause of preventable death. Recent research has underscored the important role of specific cholinergic nicotinic receptor subunit (CHRN) genes in risk for nicotine dependence and smoking. To detect and characterize the influence of genetic variation on vulnerability to nicotine dependence, we analyzed 226 SNPs covering the complete family of 16 CHRN genes, which encode the nicotinic acetylcholine receptor (nAChR) subunits, in a sample of 1,050 nicotine-dependent cases and 879 non-dependent controls of European descent. This expanded SNP coverage has extended and refined the findings of our previous large-scale genome-wide association and candidate gene study. After correcting for the multiple tests across this gene family, we found significant association for two distinct loci in the CHRNA5-CHRNA3-CHRNB4 gene cluster, one locus in the CHRNB3-CHRNA6 gene cluster, and a fourth, novel locus in the CHRND-CHRNG gene cluster. The two distinct loci in CHRNA5-CHRNA3-CHRNB4 are represented by the non-synonymous SNP rs16969968 in CHRNA5 and by rs578776 in CHRNA3, respectively, and joint analyses show that the associations at these two SNPs are statistically independent. Nominally significant single-SNP association was detected in CHRNA4 and CHRNB1. In summary, this is the most comprehensive study of the CHRN genes for involvement with nicotine dependence to date. Our analysis reveals significant evidence for at least four distinct loci in the nicotinic receptor subunit genes that each influence the transition from smoking to nicotine dependence and may inform the development of improved smoking cessation treatments and prevention initiatives.

Nicotinic receptor gene variants influence susceptibility to heavy smoking.

Heavy smoking is a strong predictor of nicotine dependence, which is a major impediment to smoking cessation. Although both heavy smoking and nicotine dependence are highly heritable, previous attempts to identify genes influencing these phenotypes have been largely unsuccessful until very recently. We studied 1,452 heavy smokers (defined as smoking at least 30 cigarettes per day for at least 5 years) and 1,395 light smokers (defined as smoking <5 cigarettes per day for at least 1 year) to investigate the association of common variants in nicotinic receptor subunit genes with smoking behavior. Compared with the most common allele, two separate groups of single nucleotide polymorphisms (SNP) in the CHRNA5-CHRNA3-CHRNB4 gene cluster were associated with heavy smoking with a very high statistical significance. One group of eight SNPs, which included a nonsynonymous SNP in the CHRNA5 gene, was in strong linkage disequilibrium and associated with increased risk of heavy smoking. A second group of SNPs not strongly correlated with the first was associated with decreased risk of heavy smoking. Analyses that combined both groups of SNPs found associations with heavy smoking that varied by >2-fold. Our findings identify two loci in the CHRNA5-CHRNA3-CHRNB4 gene cluster that predict smoking behavior and provide strong evidence for the involvement of the alpha5 nicotinic receptor in heavy smoking.

In search of causal variants: refining disease association signals using cross-population contrasts.

BACKGROUND: Genome-wide association (GWA) using large numbers of single nucleotide polymorphisms (SNPs) is now a powerful, state-of-the-art approach to mapping human disease genes. When a GWA study detects association between a SNP and the disease, this signal usually represents association with a set of several highly correlated SNPs in strong linkage disequilibrium. The challenge we address is to distinguish among these correlated loci to highlight potential functional variants and prioritize them for follow-up. RESULTS: We implemented a systematic method for testing association across diverse population samples having differing histories and LD patterns, using a logistic regression framework. The hypothesis is that important underlying biological mechanisms are shared across human populations, and we can filter correlated variants by testing for heterogeneity of genetic effects in different population samples. This approach formalizes the descriptive comparison of p-values that has typified similar cross-population fine-mapping studies to date. We applied this method to correlated SNPs in the cholinergic nicotinic receptor gene cluster CHRNA5-CHRNA3-CHRNB4, in a case-control study of cocaine dependence composed of 504 European-American and 583 African-American samples. Of the 10 SNPs genotyped in the r2 > or = 0.8 bin for rs16969968, three demonstrated significant cross-population heterogeneity and are filtered from priority follow-up; the remaining SNPs include rs16969968 (heterogeneity p = 0.75). Though the power to filter out rs16969968 is reduced due to the difference in allele frequency in the two groups, the results nevertheless focus attention on a smaller group of SNPs that includes the non-synonymous SNP rs16969968, which retains a similar effect size (odds ratio) across both population samples. CONCLUSION: Filtering out SNPs that demonstrate cross-population heterogeneity enriches for variants more likely to be important and causative. Our approach provides an important and effective tool to help interpret results from the many GWA studies now underway.

Gamma-aminobutyric acid receptor genes and nicotine dependence: evidence for association from a case-control study.

AIMS: The gamma-aminobutyric acid receptor A (GABRA) gene clusters on chromosomes 4 and 5 have been examined previously for their association with alcohol and drug dependence phenotypes. Compelling evidence suggests that GABRA2 is associated with alcohol and drug dependence. However, no study has investigated whether genes in the GABA(A) gene clusters are associated with nicotine dependence, an important phenotype with a high correlation to persistent smoking, the single most preventable cause of mortality world-wide. DESIGN: Using data on 1050 nicotine-dependent cases and 879 non-dependent smoking controls, we used logistic regression to examine the association between single nucleotide polymorphisms (SNPs) in 13 genes in the GABA(A) receptor system as well as GABBR2 (a GABA(B) gene). FINDINGS: We found evidence for association between four SNPs in GABRA4, two SNPs in GABRA2 and one SNP in GABRE with nicotine dependence. These included a synonymous polymorphism in GABRA2 (rs279858), lying in a highly conserved region, which has been shown previously to be associated with alcohol and drug dependence. A non-synonymous polymorphism (rs16859834/rs2229940) in GABRA4, also highly conserved, was associated at P-value of 0.03. Significant haplotypes associated with nicotine dependence were found for GABRA2. No evidence for epistatic interactions were noted. Our study did not find evidence for an association between GABBR2 gene and nicotine dependence. CONCLUSIONS: Given the potential role of compounds that enhance GABAergic neurotransmission in smoking cessation research, these findings have enormous potential for informing the wider field of addiction research.

Linkage scan for quantitative traits identifies new regions of interest for substance dependence in the Collaborative Study on the Genetics of Alcoholism (COGA) sample.

Dependence on alcohol and illicit drugs frequently co-occur. Results from a number of twin studies suggest that heritable influences on alcohol dependence and drug dependence may substantially overlap. Using large, genetically informative pedigrees from the Collaborative Study on the Genetics of Alcoholism (COGA), we performed quantitative linkage analyses using a panel of 1717 SNPs. Genome-wide linkage analyses were conducted for quantitative measures of DSM-IV alcohol dependence criteria, cannabis dependence criteria and dependence criteria across any illicit drug (including cannabis) individually and in combination as an average score across alcohol and illicit drug dependence criteria. For alcohol dependence, LOD scores exceeding 2.0 were noted on chromosome 1 (2.0 at 213 cM), 2 (3.4 at 234 cM) and 10 (3.7 at 60 cM). For cannabis dependence, a maximum LOD of 1.9 was noted at 95 cM on chromosome 14. For any illicit drug dependence, LODs of 2.0 and 2.4 were observed on chromosome 10 (116 cM) and 13 (64 cM) respectively. Finally, the combined alcohol and/or drug dependence symptoms yielded LODs >2.0 on chromosome 2 (3.2, 234 cM), 10 (2.4 and 2.6 at 60 cM and 116 cM) and 13 (2.1 at 64 cM). These regions may harbor genes that contribute to the biological basis of alcohol and drug dependence.

Association studies between common variants in prolyl isomerase Pin1 and the risk for late-onset Alzheimer's disease.

Alzheimer's disease (AD) pathology is associated with two proteins, the microtubule-binding protein tau and the beta-amyloid-precursor protein (APP). When tau becomes hyperphosphorylated, it forms neuritic aggregates, called neurofibrillary tangles. APP is cleaved by several enzymes to generate Abeta peptides, which are - depending on their length - more or less amyloidogenic and form senile plaques. Pin1, a peptidyl-propyl cis/trans-isomerase, seems to be involved in both pathologies. Pin1 may facilitate dephosphorylation of tau by PP2A phosphatase, while cellular overexpression of Pin1 causes a reduction in the amyloidogenic processing of APP, making this enzyme an interesting target for pharmaceutical intervention. The gene encoding Pin1 maps to 19p13.2, a region previously linked to late-onset Alzheimer's disease (LOAD). Therefore, Pin1 is an excellent positional and functional candidate for LOAD. In this study, we investigated whether common single nucleotide polymorphisms (SNPs) in Pin1 can influence the risk for developing late-onset Alzheimer's disease. No association was observed with any of six polymorphisms or their resulting haplotypes. A meta-analysis of two promoter SNPs, which combined the data from this study with two previous ones, did not show any association either suggesting that common SNPs in Pin1 do not increase the risk for LOAD.

Alcohol dependence with comorbid drug dependence: genetic and phenotypic associations suggest a more severe form of the disorder with stronger genetic contribution to risk.

BACKGROUND: Twin data suggest that alcohol dependence comorbid with illicit drug dependence represents a more heritable form of the disorder. In the Collaborative Study on the Genetics of Alcoholism sample, approximately half the alcohol-dependent individuals also meet diagnostic criteria for illicit drug dependence. In this study, we tested for heterogeneity in the association between the muscarinic acetylcholine M2 receptor gene (CHRM2) and alcohol dependence, reported previously in the full sample, among the subgroups of alcohol-dependent individuals with and without comorbid drug dependence. METHODS: Family-based association tests were conducted separately (a) in individuals with alcohol dependence with comorbid drug dependence (n = 477) and (b) in individuals with alcohol dependence without comorbid drug dependence (n = 433). These subgroups were subsequently compared on other phenotypic characteristics. RESULTS: The evidence for association between CHRM2 and alcohol dependence came entirely from the subgroup of individuals with comorbid drug dependence. There was no evidence of association with CHRM2 among the alcohol-dependent individuals without drug dependence. Subsequent phenotypic analyses suggest that the subgroup of alcohol-dependent individuals with comorbid drug dependence differ on a number of other phenotypic characteristics, including several measures of the severity of their alcohol problems, personality traits and comorbid psychiatric disorders. CONCLUSIONS: These analyses provide specific genetic evidence suggesting that alcohol dependence with comorbid drug dependence represents a particularly severe form of the disorder, with higher genetic contribution to vulnerability.

Marital status, alcohol dependence, and GABRA2: evidence for gene-environment correlation and interaction.

OBJECTIVE: The gene GABRA2 has been associated with the risk for alcohol dependence in independent samples. This article explores how this genetic risk factor interacts with marital status, another factor previously shown to be associated with the risk for alcohol dependence. METHOD: Data from more than 1,900 male and female subjects from the Collaborative Study of the Genetics of Alcoholism (COGA) sample were analyzed. Subjects were recruited based on membership in a family with multiple individuals with alcoholism. A series of analyses was performed to evaluate the relationship between the following: (1) GABRA2 and alcohol dependence, (2) marital status and alcohol dependence, (3) GABRA2 and marital status, and (4) interactions between GABRA2 and marital status on the development of alcohol dependence in the high-risk COGA sample. Additional analyses were carried out in a sample of approximately 900 individuals from control families to test the generalizability of results. RESULTS: Both GABRA2 and marital status contributed independently to the development of alcohol dependence in the COGA sample. The high-risk genotype at GABRA2 was also related to a decreased likelihood of marrying and an increased likelihood of divorce, which appeared to be mediated in part by personality characteristics. There was also differential risk associated with the GABRA2 genotype according to marital status. CONCLUSIONS: These analyses provide evidence of both gene-environment correlation and gene-environment interaction associated with GABRA2, marital status, and alcohol dependence. They illustrate the complex pathways by which genotype and environmental risk factors act and interact to influence alcohol dependence and challenge traditional conceptualizations of "environmental" risk factors.