RESUMO
We defined interpopulation differences in the frequency of the dopamine D2 receptor DRD2/Taq1 A1 allele, which has previously been associated with alcoholism. Frequencies of the A1 allele in unrelated subjects were 0.18 to 0.20 (se = 0.02 to 0.03) in several Caucasian populations previously assessed, 0.38 (+/- 0.05) in American Blacks (n = 44), 0.63 (+/- 0.07) in Jemez Pueblo Indians (n = 23), and 0.80 (+/- 0.04) in Cheyenne Indians (n = 52). The existence of large interpopulation differences in the frequency of the Taq1 alleles suggests that associations to disease status could readily be generated or masked if disease and control groups were uneven in ethnic composition. To address the possibility that the 4-fold higher frequency of the A1 allele in Cheyenne Indians was related to an increased vulnerability to alcoholism in that population, 47 Cheyenne Indians were psychiatrically interviewed and blind-rated. However, there was no significant difference between interviewed controls (0.73 +/- 0.06, n = 24), subjects with alcoholism and/or drug abuse (0.74 +/- 0.06, n = 23) and noninterviewed population controls (0.87 +/- 0.05, n = 20). Legitimate association of the DRD2/Taq1 allele to alcoholism would presumably require it to be in linkage disequilibrium (nonrandom association) with a functional mutation at DRD2 or elsewhere. The level of disequilibrium would vary between populations and could place an upper bound on the strength of an association.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Alcoolismo/genética , Genótipo , Indígenas Norte-Americanos/genética , Desequilíbrio de Ligação , Receptores de Dopamina D2/genética , Adulto , Alelos , População Negra , Frequência do Gene , Marcadores Genéticos/genética , Humanos , Modelos GenéticosRESUMO
Nineteen polymorphic lymphocyte proteins were previously detected by two-dimensional protein electrophoresis (2DE). In this report, we describe the genetic linkage mapping of six of these polymorphic proteins (PNIA1-PNIA6), the identification by genetic linkage of a seventh (glyoxalase 1 on 6p21), and support for the mapping of an eighth (plastin or LCP1) to near the ESD locus on Chr 13. PNIA1-PNIA6 were assigned, respectively, to 10q26, 16p13.3, 10q, 11p15, 3q, and 19q13. These genetic linkages were achieved by classical linkage analysis of 2DE protein charge polymorphisms to the panel of RFLPs previously typed in nine pedigrees in the Centre D'Etude du Polymorphisme Humain (CEPH) collection.
Assuntos
Proteínas Sanguíneas/genética , Polimorfismo Genético , Linhagem Celular , Mapeamento Cromossômico , Eletroforese em Gel Bidimensional , Humanos , Ponto Isoelétrico , Linfócitos/metabolismo , Polimorfismo de Fragmento de RestriçãoRESUMO
As more coding loci for functional human genes are described, there is a growing need to identify DNA polymorphisms in specific genes. By examining DNA sequences within the introns of the beta 1 subunit of the gamma-aminobutyric acid receptor gene, GABARB1, we found a tetranucleotide repeat sequence (GATA). Amplification of this region by using PCR revealed seven alleles and a high degree of polymorphism (PIC = .75) in human populations. DNAs from the CEPH families were typed for the GABARB1 intron polymorphism and were analyzed with respect to 20 linked markers on chromosome 4. The results permit placement of GABARB1 on the linkage map of chromosome 4, between D4S104 and ALB. These results affirm that sequence analysis of noncoding segments included within or adjacent to functional genes has value as a strategy to detect highly informative polymorphisms.
Assuntos
Mapeamento Cromossômico , Cromossomos Humanos Par 4 , Polimorfismo Genético , Receptores de GABA-A/genética , Sequências Repetitivas de Ácido Nucleico , Alelos , Sequência de Bases , Clonagem Molecular , DNA Satélite/genética , Feminino , Ligação Genética , Humanos , Íntrons/genética , Masculino , Dados de Sequência Molecular , Reação em Cadeia da PolimeraseRESUMO
Using the dopamine D2 receptor clone lambda hD2G1, Blum et al recently found that the D2/Taq I allele (A1) was present in 69% of 35 deceased alcoholics but in only 20% of an equal number of controls. To assess this association further, we evaluated the D2/Taq I polymorphism and a single-strand conformation polymorphism detected by polymerase chain reaction and nondenaturing gel electrophoresis (PCR-SSCP) of the 3' noncoding region of the D2 receptor gene. We studied 40 unrelated white alcoholics, 127 racially matched controls, and two white pedigrees. The Schedule for Affective Disorders and Schizophrenia-Lifetime Version (SADS-L) clinical diagnostic interviews were rated blindly by two clinicians. The SADS-L interviews and other data were then used to ascertain diagnoses according to the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition (DSM-III-R) criteria. Alcoholics were subtyped according to age of onset, severity, presence of antisocial personality, and family history. No significant differences in either D2/Taq I or PCR-SSCP allele frequencies were observed between alcoholics, subpopulations of alcoholics, or controls. The PCR-SSCP polymorphism provided independent information against linkage at the D2 receptor locus. Several recombinants between the D2/Taq I locus and alcoholism were observed in two white families with an alcoholic parent who possessed the A1 allele. This study does not support a widespread or consistent association between the D2 receptor gene and alcoholism.
