Suggestive Linkage on Chromosome 1 for a Quantitative Alcohol-Related Phenotype

Abstract

Background: Alcohol dependence is a clinically and etiologically heterogeneous disorder. Accordingly, a variety of subtypes of alcohol-dependent individuals have been proposed, and multiple operational definitions of alcohol use, abuse, and dependence have been used in linkage analyses directed toward detecting genes involved in alcohol use and problems. Here, we develop quantitative phenotypes that characterize drinking patterns among both alcoholic and nonalcoholic subjects, and use these phenotypes in subsequent linkage analyses.Methods: More than 9000 individuals from alcoholic and control families were administered a semistructured interview and personality questionnaire as part of the initial stage of the Collaborative Study on the Genetics of Alcoholism (COGA). A principal component analysis was conducted on items that captured many of the dimensions of drinking and related behaviors, including aspects of alcohol use, antisocial behavior and affective disturbance when drinking, and personality. Factor scores were computed for all individuals. Nonparametric linkage analyses were conducted on these factor scores, in the initial COGA sample consisting of 987 individuals from 105 extended families, and in a replication sample consisting of 1295 individuals from 157 extended families.Results: Three factors were identified, accounting for 68% of the total variance. The most promising regions of linkage appeared for factor 2, on which higher scores indicate a later age of onset of regular drinking and higher harm avoidance. Chromosome 1 yielded consistent evidence of linkage in both samples, with a maximum lod score of 3.3 when the samples were combined for analysis. Consistent suggestion of linkage also was found to chromosome 15.Conclusions: Developing novel phenotypes that more accurately model the effect of influential genes may help efforts to detect genes involved in complex disorders. Applying principal component analysis in the COGA sample provided support for some regions of linkage previously reported in COGA, and identified other new, promising regions of linkage.

Genomic regions linked to alcohol consumption in the Framingham Heart Study

“…Regions of the genome that have been identified as nominally linked to phenotypes related to alcohol consumption include chromosome 1 (~170 cM) and chromosome 7 (~80–100 cM) for alcohol dependence [13,14], chromosome 1 (~200–250 cM) and chromosome 15 (~70 cM) with a factor composed of later age of onset of drinking and increased harm avoidance [15], chromosome 4 (~120 cM) for alcohol consumption [16], chromosome 1 (~100–150 cM) for alcoholism or depression [17], chromosome 1 (~100–150 cM) and chromosome 21 (~80 cM) for alcohol sensitivity [18], all in the COGA sample [13], and chromosome 4 (~70 cM) and chromosome 11 (~0 cM) in the NIDDK/NIAAA American Indian sample [19]. Regions identified in this analysis of maximum alcohol consumption in the Framingham sample that correspond to the regions identified in the literature include chromosomes 1 [15], 4 [18], 7 [16], and 15 [15]. Regions of the genome that have been identified as nominally linked to phenotypes related to cigarette consumption in other samples include chromosome 1 (~0 cM), chromosome 2 (~90 cM), chromosome 14 (~95 cM) for ever-smoking in the COGA sample [20], and chromosome 2 (~145 cM) and chromosome 10 (~120 cM) in the Christchurch sample [21].…”

Candidate genes, pathways and mechanisms for alcoholism: an expanded convergent functional genomics approach

“…83 Our data show that alcohol-preferring rats have a higher baseline level of TFRC than alcohol-non-preferring rats in the HIP, and that those levels are increased by the administration of alcohol ( Table 2). TFRC maps to a locus on 3q29 that has been implicated in alcoholism, 84 as well as in bipolar disorder and schizophrenia. [85][86][87] Moreover, TFRC gene expression was reported to be altered in post-mortem brains of human alcoholics.…”

Polymorphisms in ABLIM1 are Associated with Personality Traits and Alcohol Dependence

“…A significant linkage between HA and a locus on chromosome 8p21-23 explained 38% of the trait variance. Using the Collaborative Study on the Genetics of Alcoholism (COGA) data, the second factor score, on which higher scores indicate a later age of onset of regular drinking and higher harm avoidance, showed suggestive linkages on chromosomes 1 and 15 (Dick et al 2002). These motivated researchers to search for genes for personality traits.…”