Genome-wide association study identifies 5q21 and 9p24.1 (<Emphasis Type="Italic">KDM4C</Emphasis>) loci associated with alcohol withdrawal symptoms

Several genome-wide association (GWA) studies of alcohol dependence (AD) and alcohol-related phenotypes have been conducted; however, little is known about genetic variants influencing alcohol withdrawal symptoms (AWS). We conducted the first GWA study of AWS using 461 cases of AD with AWS and 408 controls in Caucasian population in the Collaborative Study on the Genetics of Alcoholism (COGA) sample. Logistic regression analysis of AWS as a binary trait, adjusted for age and sex, was performed using PLINK. We identified 51 SNPs associated with AWS with p < 10⁻⁴. The first best signal was rs770182 (p = 3.65 × 10⁻⁶) at 5q21 near EFNA5 gene which was replicated in the Australian twin-family study of 273 families (p = 0.0172). Furthermore, three SNPs (rs10975990, rs10758821 and rs1407862) within KDM4C gene at 9p24.1 showed p < 10⁻⁴ (p = 7.15 × 10⁻⁶, 2.79 × 10⁻⁵ and 4.93 × 10⁻⁵, respectively) in the COGA sample while one SNP rs12001158 within KDM4C with p = 1.97 × 10⁻⁴ in the COGA sample was replicated in the family sample (p = 0.01). Haplotype analysis further supported the associations of single-marker analyses of KDM4C in the COGA sample. Moreover, two SNPs (rs2046593 and rs10497668) near FSIP2 at 2q32.1 with moderate associations with AWS in the COGA sample (p = 2.66 × 10⁻⁴ and 9.48 × 10⁻⁵, respectively) were replicated in the family sample (p = 0.0013 and 0.0162, respectively). In addition, several SNPs in GABRA1, GABRG1, and GABRG3 were associated with AWS (p < 10⁻²) in the COGA sample. In conclusion, we identified several loci associated with AWS. These findings offer the potential for new insights into the pathogenesis of AD and AWS.     

Family-based association analysis of alcohol dependence in the COGA sample and replication in the Australian twin-family study

Family, twin, and adoption studies have indicated that genetic and environmental factors contribute to the development of alcohol dependence (AD). We conducted a low-density genome-wide association analysis to identify genetic variants influencing AD. We used 11,120 SNPs from the Affymetrix 10K Genechips genotyped in 116 Caucasian pedigrees (272 nuclear families) from Genetic Analysis Workshop 14, a subset from the Collaborative Study on the Genetics of Alcoholism (COGA). Family-based association analyses for AD were performed by the PBAT program for autosomal SNPs and by the FBAT program for X-chromosome SNPs. We identified 37 SNPs associated with AD (P < 10⁻³), thirteen of which were located in known genes. The most significant association with AD was observed with SNP rs1986644 (P = 8.51 × 10⁻⁶) at 13q22 near EDNRB gene. The next best signal was at 1q41 in USH2A (rs532342, P = 1.07 × 10⁻⁵) and the third region was at 3q25.31 in TIPARP (rs1367311, P = 2.31 × 10⁻⁵). Furthermore, we found support for association of MAOA gene (P = 4.14 × 10⁻⁴ for rs979606). Six of the 37 AD associated SNPs were confirmed to be associated with AD in Australian twin-family study sample (P < 0.05). Interestingly, four SNPs in DSCAML1 at 11q23 reached the genome-wide significance (the top SNP is rs10892169 with P = 5.31 × 10⁻⁹), while rs637547 in NKAIN2 at 6q21 showed strong association with AD (P = 5.11 × 10⁻⁷) in the replication sample. These findings offer the potential for new insights into the pathogenesis of AD and will serve as a resource for replication in other populations to elucidate the potential role of these genetic variants in AD.     

Common Variants in HLA-DRA Gene are Associated with Alcohol Dependence in Two Caucasian Samples

HLA-DRA gene polymorphisms might play an important role in alcohol dependence (AD). We examined genetic associations of 29 single-nucleotide polymorphisms (SNPs) within the HLA-DRA gene with AD using two Caucasian samples—the Collaborative Study on the Genetics of Alcoholism (COGA) sample (660 AD cases and 400 controls) and the Study of Addiction: Genetics and Environment (SAGE) sample (623 cases and 1,016 controls). Logistic regression analysis using PLINK showed that 16 SNPs were associated with AD in the COGA sample and 13 SNPs were associated with AD in the SAGE sample (p?<?0.05). The best novel signal was SNP rs2239803 associated with AD in both samples (p?=?0.000817 for the COGA sample and p?=?0.0026 for the SAGE sample, respectively) while one flanking SNP rs4935356 also showed strong association in both samples (p?=?0.00219 and 0.0026 for the COGA and SAGE samples, respectively). Furthermore, these two SNPs revealed stronger associations in meta-analysis of these two samples (p?=?8.97?×?10^?6 and 2.02?×?10^?5 for rs2239803 and rs4935356, respectively). In addition, the G-A haplotype from these two SNPs revealed a significant association with AD in both the COGA and SAGE samples (p?=?0.0007 and 0.0019, respectively). These findings highlight the novel associations with HLA-DRA that may play an important role in the etiology of AD.     

Fyn Polymorphisms are Associated with Distinct Personality Traits in Healthy Chinese-Han Subjects

The Src family tyrosine kinase Fyn regulates a myriad of neurophysiological processes, including learning and memory. To date, the role of Fyn in the neurological mechanisms that determine personality traits has not been addressed. To this end, we determined the association between the rs706895C/T polymorphism of the Fyn gene (FYN) and personality traits measured by the Tridimensional Personality Questionnaire in 502 healthy Chinese-Han subjects. There were no significant differences in the total scores for novelty seeking (χ ² = 5.12, P = 0.077), harm avoidance (HA; χ ² = 2.63, P = 0.269), or reward dependence (RD; χ ² = 3.94, P = 0.139) among the rs706895C/T genotypes. In sub-item analyses, however, both fear of uncertainty (HA2; χ ² = 7.84, P = 0.020) and sentimentality (RD1; χ ² = 8.27; P = 0.016) scores were significantly different among rs706895C/T genotypes. Our results suggest that FYN alleles can contribute to the variance in human personality traits.     

Insulin,glucose and glycated hemoglobin in Alzheimer’s and vascular dementia with and without superimposed Type II diabetes mellitus condition

Summary. Increased concentrations of insulin, glucose and glycohemoglobin are associated with Type II diabetes mellitus (DM) and recognized as characteristic markers of the disease; in Alzheimer’s (AD), Vascular dementia (VaD), and both dementia’s with superimposed diabetes (AD + DM, VaD + DM) the knowledge is scarce. The sample (n = 122; males = 60; mean age = 73 ± 7) comprised DM, AD, VaD, AD + DM, and VaD + DM patients, and healthy controls (C). The ANOVA’s yielded significant differences between groups: Insulin p = 3.7 × 10⁻³; Glucose p < 10⁻¹²; Glycohemoglobin p = 9.2×10⁻⁴. Comparisons between groups (DM vs. C, AD + DM vs. AD, VaD + DM vs. VaD, and demented DM vs. non-demented DM) resulted significant for all variables (Bonferroni’s statistic, α = 0.05). Diabetic and diabetic demented patients presented significant increases largely different from controls (0.01 < p < 0.001), unlike the non-significant changes in their non-diabetic counterparts; linear relationships were found across all groups. The correlation’s insulin/glucose and insulin/glycohemoglobin change to positive within demented groups, indicating a different performance of insulin in demented and non-demented subjects. Integrated by the following medical degrees (MD) and psychologists (Ps) from the Neurology Service and the Diabetes Unit of the Hospital General de Agudos Juan A. Fernández, Hospital Sirio-Libanés and the FACENE: Eduardo L. Bartolomé MD, Silvia González MD, Graciela D’Abraccio MD, Marcela Arata Ps, Liliana Oudkerk Ps, Laura Garau MD, Fernando Krinsky MD, Edith Labos Ps, Cecilia Ruiz Ps, Gustavo Frechtel MD, Alejandra Arana MD, and Silvia Lovecchio MD. Correspondence: Jorge A. Serra, Laboratorio de Estrés Oxidativo, PRALIB-CONICET, Facultad de Farmacia y Bioquímica, UBA; Junín 954; C1113AAD Buenos Aires, Argentina     

Reduced CSF carboxyterminally truncated Aβ peptides in frontotemporal lobe degenerations

Summary. Cerebrospinal fluid (CSF) carboxyterminally truncated amyloid-beta (Aβ) peptides, Aβ1-42 and tau protein were evaluated in 30 patients with frontotemporal lobe degenerations (FTLD), 30 Alzheimer’s disease (AD) patients and 30 non-demented disease controls (NDC) by Aβ-SDS-PAGE/immunoblot as well as commercial ELISAs for Aβ1-42 and total tau. FTLD displayed a significant drop of Aβ1-37 (p = 2.7 × 10⁻⁴), Aβ1-38 (p = 4.2 × 10⁻⁵) and Aβ1-42 (p = 3.3 × 10⁻⁴). Aβ1-42 was selectively decreased in AD (p = 8.5 × 10⁻¹⁰). Decreased Aβ1-38 enabled contrasts of beyond 85% to distinguish FTLD from AD and NDC patients, alone or in combination. Accordingly, low CSF Aβ1-37 and Aβ1-38 represent a biomarker candidate for FTLD and may reflect disease-specific changes of APP metabolism. Further validation should be carried out on dementias other than AD, diagnostically relevant control groups without dementia and without any evident affection of the central nervous system and subgroups of FTLD. Moreover, independent methods of measurement should be applied to CSF Aβ1-38.     

Correlation of BDNF blood levels with interoceptive awareness and maturity fears in anorexia and bulimia nervosa patients

Association studies and rodent models suggest a major role for BDNF (brain-derived neurotrophic factor) in feeding regulation. Altered BDNF blood levels have been associated with eating disorders (ED) and their related psychopathological traits. Since the influence of BDNF on self-reported eating disorder inventory scores (EDI) has not been tested, we investigated the correlation of EDI scales with BDNF plasma levels. BDNF levels were measured by (ELISA), and the EDI questionnaire was administered in a total of 81 ED patients. The relationship between BDNF levels and EDI scores was calculated using a general linear model. After correcting for multiple testing, BDNF plasma levels negatively correlated with the EDI total score (R ² = 0.26; p = 4.09 × 10⁻⁴), interoceptive awareness (R ² = 0.26; p = 1.96 × 10⁻⁴), and maturity fears (R ² = 0.13; p = 6.92 × 10⁻⁴). When subdividing according to the main diagnoses, interoceptive awareness presented significant correlations with BDNF blood levels in both the anorexia nervosa (R ² = 0.33, p = 0.0026) and bulimia nervosa groups (R ² = 0.10; p = 0.008). Our data suggest that BDNF levels may influence the severity of the ED by modulating the associated psychopathology, in particular through the impairment of interoceptive awareness.     

The premorbid personality of patients with Parkinson's disease: evidence with the Tridimensional Personality Questionnaire

The premorbid personality traits of 102 patients with Parkinson's disease (PD) and 57 age-matched healthy controls were studied by the recently developed Tridimensional Personality Questionnaire. We found significantly fewer (p < 0.05) of a group of traits called “novelty seeking” (NS), but no changes in “harm avoidance” (HA) and “reward dependence” (RD), in PD patients, for the period approximately 5–10 years before the onset of the disease, compared to controls. Individuals who are lower than average in NS and average in HA and RD are described as reflective, rigid, loyal, stoic, slow-tempered, frugal, orderly, and persistent Since NS is thought to be directly related to central dopaminergic reactivity, the premorbid expression of these behaviors may be the reflection of neurochemical deficits (hypodopaminergic tone) accompanying the presymptomatic phase of PD.     

Association study of cholesterol-related genes in Alzheimer’s disease

Alzheimer’s disease (AD) is a genetically complex disorder, and several genes related to cholesterol metabolism have been reported to contribute to AD risk. To identify further AD susceptibility genes, we have screened genes that map to chromosomal regions with high logarithm of the odds scores for AD in full genome scans and are related to cholesterol metabolism. In a European screening sample of 115 sporadic AD patients and 191 healthy control subjects, we analyzed single nucleotide polymorphisms in 28 cholesterol-related genes for association with AD. The genes HMGCS2, FDPS, RAFTLIN, ACAD8, NPC2, and ABCG1 were associated with AD at a significance level of P ≤ 0.05 in this sample. Replication trials in five independent European samples detected associations of variants within HMGCS2, FDPS, NPC2, or ABCG1 with AD in some samples (P = 0.05 to P = 0.005). We did not identify a marker that was significantly associated with AD in the pooled sample (n = 2864). Stratification of this sample revealed an APOE-dependent association of HMGCS2 with AD (P = 0.004). We conclude that genetic variants investigated in this study may be associated with a moderate modification of the risk for AD in some samples. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Further examination of the candidate genes in chromosome 12p13 locus for late-onset Alzheimer disease

A broad region on chromosome 12p13 has been intensely investigated for novel genetic variants associated with Alzheimer disease (AD). We examined this region with 23 microsatellite markers using 124 North European (NE) families and 209 Caribbean Hispanic families with late-onset AD (FAD). Significant evidence for linkage was present in a 5-cM interval near 20 cM in both the NE FAD (LOD = 3.5) and the Caribbean Hispanic FAD (LOD = 2.2) datasets. We further investigated these families and an independent NE case–control dataset using 14 single nucleotide polymorphisms (SNPs). The initial screening of the region at ∼20 cM in the NE case–control dataset revealed significant association between AD and seven SNPs in several genes, with the strongest result for rs2532500 in TAPBPL (p = 0.006). For rs3741916 in GAPDH, the C allele, rather than the G allele as was observed by Li et al. (Proc Natl Acad Sci U S A 101(44):15688–15693, 2004), was the risk allele. When the two family datasets were examined, none of the SNPs were significant in NE families, but two SNPs were associated with AD in Caribbean Hispanics: rs740850 in NCAPD2 (p = 0.0097) and rs1060620 in GAPDH (p = 0.042). In a separate analysis combining the Caribbean Hispanic families and NE cases and controls, rs740850 was significant after correcting for multiple testing (empirical p = 0.0048). Subsequent haplotype analyses revealed that two haplotype sets—haplotype C-A at SNPs 6–7 within NCAPD2 in Caribbean Hispanics, and haplotypes containing C-A-T at SNPs 8–10 within GAPDH in Caribbean Hispanic family and NE case–control datasets—were associated with AD. Taken together, these SNPs may be in linkage disequilibrium with a pathogenic variant(s) on or near NCAPD2 and GAPDH. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Association of NAD(P)H:Quinone Oxidoreductase 1 Polymorphism and Alzheimer’s Disease in Chinese

Several lines of evidence support a role of oxidative stress in the pathology of Alzheimer’s disease (AD). NAD(P)H:quinone oxidoreductase 1 (NQO1) catalyzes the two-electron reduction of quinones, preventing their participation in redox cycling and subsequent generation of reactive oxygen species. We examined association between the NQO1 C609T gene polymorphism and sporadic AD in a Chinese population comprising 311 AD patients and 330 controls. Our results showed a higher T-allele frequency in the AD cases compared with the controls. The difference was close to but did not reach statistically significant level [p = 0.059; odds ratio (OR) T versus C = 1.236; 95% confidence interval (95% CI), 0.992–1.540]. A significantly low C/C genotype frequency in the AD cases compared with the controls was detected (p = 0.025; OR C/C versus C/T + T/T = 0.674; 95% CI, 1.049–2.098) and APOE ε4 status analysis revealed significant difference in the APOE ε4 non-carriers (p = 0.036; OR = 0.633; 95% CI, 1.027–2.427). In the ≥65 years samples, significantly low C/C frequency in the AD cases in comparison with the controls was observed in the APOE ε4 non-carriers (p = 0.045; OR = 0.595; 95% CI, 1.010–2.794). These results indicated that the C/C genotype had a possible protective effect against AD development, and the T allele might be a weak risk factor for late onset AD. J-T Bian and H-L Zhao contributed equally to the work.     

Epidemiology of Duchenne muscular dystrophy in the province of Turin

An epidemiological investigation on Duchenne muscular dystrophy in Turin and its province has been carried out for the period 1955–1974. The incidence of the disease proved to be 24×10⁻⁵, and the prevalence 2.15×10⁻⁵. The mutation rate was 80×10⁻⁶. The data are compared with the literature. Segregation analysis on many families was performed in order to find the theoretical number of carrier among Duchenne mothers. The importance of epidemiology for genetic counselling is stressed.

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Sommario è stata condotta un'indagine epidemiologica della DMP tipo Duchenne in Torino e provincia, considerando il periodo 1955–1974. L'incidenza della malattia è risultata di 24×10⁻⁵, la prevalenza di 2.15×10⁻⁵. Il tasso di mutazione è di 80×10⁻⁶. I dati sono discussi e paragonati con quelli della letteratura. Alcune famiglie sono state sottoposte and analisi di segregazione per identifi?are il numero teorico di portatrici tra le madri Duchenne. Viene sottolineata l'importanza dell'epidemiologia in vista del genetic counselling.

     

Pilot study of ifosfamide/carboplatin/etoposide (ICE) for peripheral blood stem cell mobilization in patients with high-risk or relapsed medulloblastoma

Objectives The purpose of this study is to evaluate the stem cell mobilization capacity, anti-tumor effect, and feasibility of ifosfamide/carboplatin/etoposide (ICE) for transplant-eligible patients with medulloblastoma. Materials and methods Six patients (23 months to 18 years old) with high-risk or relapsed medulloblastoma received one cycle of ICE, which consisted of ifosfamide at 1.8 g/m² for 5 days, carboplatin 400 mg/m² for 2 days, and etoposide 100 mg/m² for 5 days. Stem cells were mobilized with ICE followed by granulocyte colony-stimulating factor at 10 μg kg⁻¹ day⁻¹. Results After one cycle of ICE, the median number of harvested CD34+ cells per apheresis session was 11.85 × 10⁶ cells/kg (range, 0.2 to 71.2 × 10⁶ cells/kg). Two patients obtained a complete response and three patients a partial response. All patients experienced severe myelosuppression, and three infectious toxicities were observed. Conclusions These results suggest that ICE is optimal for mobilizing stem cells, effective for high-risk or relapsed medulloblastoma, and tolerable with limited non-hematological toxicity.     

<Emphasis Type="Italic">PEMT</Emphasis> G523A (V175M) Is Associated with Sporadic Alzheimer's Disease in a Chinese Population

There is evidence that increased concentrations of circulating homocysteine are associated with Alzheimer's disease (AD). Phosphatidylethanolamine N-methyltransferase (PEMT) is an important catalyst involved in the production of homocysteine. We investigated the association of a functional single nucleotide polymorphism (rs7946) in PEMT with sporadic AD risk in a Han Chinese population that included 386 AD patients and 366 controls. PEMT G523A was genotyped by either sequencing or PCR-restriction fragment length polymorphism analysis. The plasma homocysteine concentrations of 210 subjects were determined by high-performance liquid chromatography. Significant higher frequency of the A allele was detected in AD cases than in controls (A vs. G, p = 0.007, OR = 1.482, 95% CI 1.114–1.972). After adjusting for gender, age/age at onset, and APOE ε4 status, logistic analysis showed rs7946 was associated with AD in a dominant model (AA + GA vs. GG, p = 0.007, OR = 1.596, 95% CI 1.138–2.240). When stratified by APOE ε4 status or gender, the significant difference was only observed in the APOE ε4 non-carriers and in the female subjects, respectively. We did not find a relationship of this polymorphism with plasma homocysteine levels. These results suggested that PEMT G523A is associated with AD and that the A allele is an APOE ε4-independent risk factor for AD among Han Chinese women.     

Association Between DARPP-32 Gene Polymorphism and Personality Traits in Healthy Chinese-Han Subjects

The 32-kDa dopamine- and cAMP-regulated phosphoprotein (DARPP-32) is a key signaling factor in several neurotransmitter pathways (including dopamine and serotonin) that impact personality traits. Therefore, different DARPP-32 alleles may influence the biological determination of distinct personality types. We established an association between the DARPP-32 gene polymorphisms (rs12601930C/T, rs879606A/G, and rs3764352A/G) and personality traits as measured by the Tridimensional Personality Questionnaire in 502 healthy Chinese-Han subjects. Of the three polymorphic sites examined, rs12601930C/T was associated with novelty seeking (χ ² = 13.06, P = 0.001), while both rs879606A/G and rs3764352A/G were associated with harm avoidance (rs879606: χ ² = 7.74, P = 0.021; rs3764352: χ ² = 8.53, P = 0.014). There was no significant association between reward dependence scores and DARPP-32 gene polymorphisms. Our results suggest that polymorphisms in the DARPP-32 gene are involved in the biological mechanisms that confer the traits of novelty seeking and harm avoidance.     

Growth hormone response in low-dose apomorphine test correlates with nigrostriatal dopamine transporter binding in patients with Parkinson’s disease

Summary. Challenge with low-dose apomorphine causes a rise in growth hormone (GH) in patients with Parkinson’s disease (PD). We studied 18 patients with early PD, who showed an increase of GH in the low-dose apomorphine test, by means of [¹²³I] FP-CIT-SPECT. The mean specific dopamine transporter binding of the 18 patients was 1.50 ± 0.56 in the striatum, 1.20 ± 0.59 in the putamen, and 1.76 ± 0.59 in the caudate nucleus. The increase of GH (1.05 ± 1.01 ng/ml at baseline to 9.46 ± 6.36 ng/ml 45 min after apomorphine injection; p < 0.001) was significant. There was a significant negative correlation of the increase of GH with the mean specific dopamine transporter binding in all three regions (r between −0.490 and −0.587; p between 0.04 and 0.01). Challenge with low-dose apomorphine may therefore be used as an indirect tool to measure the extent of nigrostriatal neurodegeneration in early PD.     

Imaging genomics discovery of a new risk variant for Alzheimer's disease in the postsynaptic SHARPIN gene

Molecular mechanisms underlying Alzheimer's disease (AD) are difficult to investigate, partly because diagnosis lags behind the insidious pathological processes. Therefore, identifying AD neuroimaging markers and their genetic modifiers may help study early mechanisms of neurodegeneration. We aimed to identify brain regions of the highest vulnerability to AD using a data‐driven search in the AD Neuroimaging Initiative (ADNI, n = 1,100 subjects), and further explored genetic variants affecting this critical brain trait using both ADNI and the younger UK Biobank cohort (n = 8,428 subjects). Tensor‐Based Morphometry (TBM) and Independent Component Analysis (ICA) identified the limbic system and its interconnecting white‐matter as the most AD‐vulnerable brain feature. Whole‐genome analysis revealed a common variant in SHARPIN that was associated with this imaging feature (rs34173062, p = 2.1 × 10^?10). This genetic association was validated in the UK Biobank, where it was correlated with entorhinal cortical thickness bilaterally (p = .002 left and p = 8.6 × 10^?4 right), and with parental history of AD (p = 2.3 × 10^?6). Our findings suggest that neuroanatomical variation in the limbic system and AD risk are associated with a novel variant in SHARPIN. The role of this postsynaptic density gene product in β1‐integrin adhesion is in line with the amyloid precursor protein (APP) intracellular signaling pathway and the recent genome‐wide evidence.     

Does apolipoprotein E (Apo-E) genotype influence nicotinic receptor binding in Alzheimer's disease

Summary. We wished to determine the influence of the apolipoprotein E (Apo-E) genotype on the loss of high affinity nicotinic acetylcholine receptor (nAChR) binding in Alzheimer's disease (AD). The interaction between ε4 allele gene dose and cholinergic loss in AD remains controversial. We have demonstrated that nicotinic binding is significantly lost in AD. Tissue from the midfrontal (MF) cortex of 7 subjects with no ε4 allele copies (ε−/ε−) (mean death age 75.1 ± 10.4 years) was compared to MF cortex of 14 subjects heterozygous for the ε4 allele (ε4/ε−) (mean death age 81.4 ± 7.3 years) and MF cortex of 10 subjects homozygous for the ε4 allele (ε4/ε4) (mean death age 79.6 ± 5.0 years). All subjects were autopsy confirmed AD (using NIA and CERAD criteria) and met NINCDS-ADRDA clinical criteria for probable or possible AD. Nicotine AChR binding was assayed using the high affinity nicotinic agonist ³H-epibatidine ([³H]-Epi). Apo-E genotype was determined in blood samples or in post-mortem tissue. The mean age at death was not significantly different among the groups (p = 0.19). There was no difference in mean [³H]-Epi total binding among the three groups (6.7 ± 4.6, 6.1 ± 2.4, and 6.0 ± 1.0 fmol/mg protein for ε−/ε−, ε4/ε−, and ε4/ε4 respectively. We conclude that the presence or absence of the Apo-E4 genotype does not influence the loss of high affinity nAChR in AD. Received January 16, 2001; accepted April 16, 2001     

Association between DPYSL2 gene polymorphisms and alcohol dependence in Caucasian samples

The DPYSL2 gene at 8p22-p21 is expressed widely in neuronal tissues and has been implicated in multiple psychiatric disorders such as Alzheimer’s disease and schizophrenia. We therefore hypothesized that DPYSL2 gene polymorphisms may play a role in alcohol dependence (AD). We investigated the genetic associations of 57 single-nucleotide polymorphisms (SNPs) within the DPYSL2 gene with AD using two Caucasian samples—the Collaborative Study on the Genetics of Alcoholism (COGA) sample (660 AD cases and 400 controls), and the Study of Addiction: Genetics and Environment (SAGE) sample (623 cases and 1,016 controls). The SNP rs11995227 was most significantly associated with AD (p = 0.000122) in the COGA sample while one flanking SNP rs7832576 revealed the second most significant association with AD (p = 0.00163) in the COGA sample and association with AD (p = 0.0195) in the SAGE sample. Meta-analysis of two samples showed both rs119952227 and rs7832576 were associated with AD (p = 0.000363 and 0.000184, respectively). Furthermore, the C-A haplotype from rs11995227 and rs7832576 revealed significant association with AD (p = 0.0000899) in the COGA sample while the T-G haplotype revealed association with AD both in the COGA and SAGE samples (p = 0.00098 and 0.021, respectively). These findings suggest that genetic variants in DPYSL2 may play a role in susceptibility to AD.