Confirmation and fine mapping of the chromosome 1 alcohol dependence risk locus

Abstract

Two previous large genetic linkage studies in the US population have implicated an area in chromosome 1p to contain a susceptibility gene for alcohol dependence. The 1-LOD support interval of the linkage signal spans about 30 cM and contains 430 000 000 DNA base pairs (bp) and 700 predicted genes. In order to reduce the size of the candidate area and potentially identify novel candidate genes within this region, we fine-mapped this area using closely spaced short tandem repeat (STR) markers and the transmission disequilibrium test (TDT) in small nuclear families. The subjects were 87 European-American families including one or more alcohol-dependent offspring (93 children and 174 parents). The initial marker set consisted of 30 STR markers, spanning the Marshfield map interval between 101.48 and 130.73 cM. Using the TDTPHASE program, we identified three markers in the distal part of this region (125-126 cM), which showed evidence of transmission disequilibrium. On the basis of this result, an additional 12 STR markers were genotyped in this region; some of these markers provided additional evidence for linkage disequilibrium. The strongest evidence for transmission disequilibrium was obtained at the marker D1S406 (P¼0.005, 126.16 cM), with supporting evidence from three neighboring STR markers D1S424 (126.16 cM, P¼0.01), D1S2804 (126.16 cM, P¼0.04), and D1S2776 (126.16 cM, P¼0.02), which are all located within a o350 000 bp interval. These findings suggest that a gene (or genes) causing susceptibility to alcohol dependence resides near location 126.16 cM on chromosome 1. In addition, these results provide independent confirmation of the linkage finding regarding the identification of at least one gene in this region increasing the risk for alcohol dependence.

Ionotropic glutamate receptor gene GRIK3 SER310ALA functional polymorphism is related to delirium tremens in alcoholics

“…20,21 This association was recently supported by a family-based study using genetic fine-mapping of the 1p region of chromosome 1. 29 Comparing gentoype frequencies in our study with previous research (Begni et al, 30 30 who reported lower genotype frequencies of the GRIK3 polymorphism Ser allele in his sample of schizophrenic patients. These patients had a very different psychiatric diagnosis of schizophrenia while the in-patient sample enrolled into this study all had a diagnosis of alcohol-dependence.…”

Kernel-Based Association Test

“…Our identified strong association signals on chromosomes 1 and 6 were close to the regions mapped by the previous studies (Edenberg et al 2004;Lappalainen et al 2004). The highest peak on chromosome 1 was close to the alcoholism gene region between D1S2779 (126.16 cM) and D1S1170 (128.73 cM) identified by Lappalainen et al (2004).…”

“…Our identified strong association signals on chromosomes 1 and 6 were close to the regions mapped by the previous studies (Edenberg et al 2004;Lappalainen et al 2004). The highest peak on chromosome 1 was close to the alcoholism gene region between D1S2779 (126.16 cM) and D1S1170 (128.73 cM) identified by Lappalainen et al (2004). The highest peak on chromosome 6 was close to the human major histocompatibility complex region that covers important alco- holism genes, such as GABRA2 (Edenberg et al 2004).…”

Involvement of cannabinoid CB2 receptor in alcohol preference in mice and alcoholism in humans

“…29 Because CMS or forced swim stress that increase ethanol preference as shown in this study and in others, 13 were also animal model of depression, 27,30 our mice and human data in this study are well suited to a model of addiction to alcoholism. The human CNR2 gene is located on chromosomes 1p36, nearby where only one report has indicated a broad and weak linkage to alcoholism, 31 although common linkage area was reported around chromosome 1p31, not very close to CNR2 locus. 32 Because our genetics data indicated that CNR2 has a moderate effect on human alcoholism and our mouse studies revealed the contributions of non genetic factors related to development of alcohol preference, it is likely that reinforcement of alcohol preference/addiction and stress may also influence endocannabinoids regulation that alters Cnr2 gene/protein expression in CNS.…”