Dense Genomewide Linkage Scan for Alcohol Dependence in African Americans: Significant Linkage on Chromosome 10

Department of Psychiatry, Division of Human Genetics, Yale University School of Medicine, New Haven, CT, USA.
Biological psychiatry (Impact Factor: 10.26). 11/2008; 65(2):111-5. DOI: 10.1016/j.biopsych.2008.08.036
Source: PubMed


Alcohol dependence (AD) is costly to societies worldwide, moderately heritable, and genetically complex. Risk loci in several populations have been identified with genetic linkage analysis. To date, there has been no published linkage study of AD focused on African Americans (AAs).
We completed a genomewide linkage scan with approximately 6000 single nucleotide polymorphism markers to map loci increasing risk for DSM-IV AD in a set of 238 small nuclear families ascertained on the basis of multiple individuals affected with cocaine or opioid dependence. Model free linkage analysis was completed with Merlin software. A modified marker set was used to avoid bias due to markers in strong linkage disequilibrium.
We identified a genomewide-significant linkage to markers near 117.2 centiMorgans on chromosome 10q23.3-24.1 (logarithm of odds score 3.32; p = 5.0E-05; empirical genomewide p = .033).
These data add to the growing evidence for locations for AD risk loci and provide the first linkage evidence for such a locus in the AA population.

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    • "Heritability estimates range from 50% to 80% [Heath et al., 1997; Knopik et al., 2004; Kendler and Prescott, 2006]. Susceptibility loci have been mapped to various chromosomes using genetic linkage methods [Reich et al., 1998; Williams et al., 1999b; Foroud et al., 2000; Nurnberger et al., 2001; Dick et al., 2002; Prescott et al., 2006; Gelernter et al., 2009], with successful gene localization occurring from the follow-up of some positive linkage regions, most notably GABRA2 and ADH4 [Edenberg et al., 2004, 2006a]. More recently, the first generation of genome-wide, case–control association studies (GWAS) revealed a number of promising SNP associations to AUD [Treutlein et al., 2009; Bierut et al., 2010; Edenberg et al., 2010; Gelernter et al., 2014], although most of the variation in genetic liability remains to be explained. "
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    ABSTRACT: Linkage studies of alcoholism have implicated several chromosome regions, leading to the successful identification of susceptibility genes, including ADH4 and GABRA2 on chromosome 4. Quantitative endophenotypes that are potentially closer to gene action than clinical endpoints offer a means of obtaining more refined linkage signals of genes that predispose alcohol use disorders (AUD). In this study we examine a self-reported measure of the maximum number of drinks consumed in a 24-hr period (abbreviated Max Drinks), a significantly heritable phenotype (h(2) = 0.32 ± 0.05; P = 4.61 × 10(-14) ) with a strong genetic correlation with AUD (ρg = 0.99 ± 0.13) for the San Antonio Family Study (n = 1,203). Genome-wide SNPs were analyzed using variance components linkage methods in the program SOLAR, revealing a novel, genome-wide significant QTL (LOD = 4.17; P = 5.85 × 10(-6) ) for Max Drinks at chromosome 6p22.3, a region with a number of compelling candidate genes implicated in neuronal function and psychiatric illness. Joint analysis of Max Drinks and AUD status shows that the QTL has a significant non-zero effect on diagnosis (P = 4.04 × 10(-3) ), accounting for 8.6% of the total variation. Significant SNP associations for Max Drinks were also identified at the linkage region, including one, rs7761213 (P = 2.14 × 10(-4) ), obtained for an independent sample of Chinese families. Thus, our study identifies a potential risk locus for AUD at 6p22.3, with significant pleiotropic effects on the heaviness of alcohol consumption that may not be population specific. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 06/2014; 165(4). DOI:10.1002/ajmg.b.32231 · 3.42 Impact Factor
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    • "Nonetheless, aforementioned association studies have suggested the implicated role of candidate genes from neurotransmitter systems, including dopaminergic, GABAergic, glutamatergic, opioid, cholinergic, and serotonergic systems. Some of these genes are located in or close to chromosomal regions (in chromosomes 1, 2, 4, 5, 7, 11, 13, and 17) indicated by linkage studies [35], [36], [37], [38]. The inconsistent results for AUD studies were considered caused by multiple AUD vulnerable genes with small and diverse effect sizes in different populations [39]. "
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    ABSTRACT: Studies of linkage and association in various ethnic populations have revealed many predisposing genes of multiple neurotransmitter systems for alcohol use disorders (AUD). However, evidence often is contradictory regarding the contribution of most candidate genes to the susceptibility of AUD. We, therefore, performed a case-control study to investigate the possible associations of genes selected from multiple neurotransmitter systems with AUD in a homogeneous Tibetan community population in China. AUD cases (N = 281) with an alcohol use disorder identification test (AUDIT) score ≥10, as well as healthy controls (N = 277) with an AUDIT score ≤5, were recruited. All participants were genotyped for 366 single nucleotide polymorphisms (SNPs) of 34 genes selected from those involved in neurotransmitter systems. Association analyses were performed using PLINK version 1.07 software. Allelic analyses before adjustment for multiple tests showed that 15 polymorphisms within seven genes were associated with AUD (p<0.05). After adjustment for the number of SNPs genotyped within each gene, only the association of a single marker (rs10044881) in HTR4 remained statistically significant. Haplotype analysis for two SNPs in HTR4 (rs17777298 and rs10044881) showed that the haplotype AG was significantly associated with the protective effect for AUD. In conclusion, the present study discovered that the HTR4 gene may play a marked role in the pathogenesis of AUD. In addition, this Tibetan population sample marginally replicated previous evidence regarding the associations of six genes in AUD.
    PLoS ONE 11/2013; 8(11):e80206. DOI:10.1371/journal.pone.0080206 · 3.23 Impact Factor
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    • "This linkage peak is located 10–15 cM proximal to a suggestive linkage peak for CD–MDE observed in the EA families. Moreover, the chromosome 10 locus for CD in the AA families is 17 and 27 cM distal from linkage peaks we found for alcohol dependence (AD) previously in the EA and AA families, respectively (Gelernter et al, 2009; Panhuysen et al, 2010). "
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    ABSTRACT: Cocaine dependence (CD) and major depressive episode (MDE) frequently co-occur with poorer treatment outcome and higher relapse risk. Shared genetic risk was affirmed; to date, there have been no reports of genomewide linkage scans (GWLSs) surveying the susceptibility regions for comorbid CD and MDE (CD-MDE). We aimed to identify chromosomal regions and candidate genes susceptible to CD, MDE, and CD-MDE in African Americans (AAs) and European Americans (EAs). A total of 1896 individuals were recruited from 384 AA and 355 EA families, each with at least a sibling-pair with CD and/or opioid dependence. Array-based genotyping of about 6000 single-nucleotide polymorphisms was completed for all individuals. Parametric and non-parametric genomewide linkage analyses were performed. We found a genomewide-significant linkage peak on chromosome 7 at 183.4 cM for non-parametric analysis of CD-MDE in AAs (lod=3.8, genomewide empirical p=0.016; point-wise p=0.00001). A nearly genomewide significant linkage was identified for CD-MDE in EAs on chromosome 5 at 14.3 cM (logarithm of odds (lod)=2.95, genomewide empirical p=0.055; point-wise p=0.00012). Parametric analysis corroborated the findings in these two regions and improved the support for the peak on chromosome 5 so that it reached genomewide significance (heterogeneity lod=3.28, genomewide empirical p=0.046; point-wise p=0.00053). This is the first GWLS for CD-MDE. The genomewide significant linkage regions on chromosomes 5 and 7 harbor four particularly promising candidate genes: SRD5A1, UBE3C, PTPRN2, and VIPR2. Replication of the linkage findings in other populations is warranted, as is a focused analysis of the genes located in the linkage regions implicated here.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 08/2011; 36(12):2422-30. DOI:10.1038/npp.2011.122 · 7.05 Impact Factor
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