American Journal of Medical Genetics最新文献

Lack of Fyn tyrosine kinase increases alcohol sensitivity. Fyn phosphorylates a component of the NMDA receptor, which may be involved in schizophrenia. The Fyn gene is located on human chromosome 6q21, to which linkage of schizophrenia has been suggested. We hypothesized that the Fyn gene is a candidate for predisposition to alcoholism and schizophrenia, and we performed a mutation study of the 5'-flanking region, all coding exons, and exon-intron junctions of the Fyn gene. The SSCP mutation analysis was performed in 48 unrelated alcoholics and 16 unrelated schizophrenics. Three polymorphisms, -93A/G in the 5'-flanking region, IVS10+37T/C in intron 10, and Ex12+894T/G in the 3'-untranslated region, were identified. A rare variant of Ex12+1162TG in the 3'-untranslated region was also detected. Neither missense nor nonsense mutations were found. Case-control studies using a larger sample of unrelated patients and controls did not reveal significant associations between these polymorphisms and alcoholism or schizophrenia. In addition, genotyping a microsatellite marker, D6S302, located in intron 10 of the Fyn gene, did not show a significant association between the marker and alcoholism or schizophrenia. Results of the present study did not provide evidence for the involvement of the genomic Fyn gene mutations in alcoholism or schizophrenia. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:716-720, 2000.

Several recent meta-analyses appear to show a weak but significant effect of both forms of the gly/ser DRD3 polymorphism in conferring risk for schizophrenia. Since most studies have employed the artifact-prone case-control design, we thought it worthwhile to examine the role of this polymorphism using a robust family-based strategy in an ethnic group not previously systematically studied in psychiatric genetics, Palestinian Arabs. We failed to obtain any evidence in 129 Palestinian triads, using the haplotype relative risk (allele frequency: Pearson chi-square = 0.009, P > 0.1, df = 1, n = 258 alleles) or transmission disequilibrium test design (chi-square = 0.38, P > 0.1, n = 86 families) for association/linkage (or increased homozygosity) of the DRD3 Bal I polymorphism to schizophrenia in our sample. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:778-780, 2000.

A number of linkage studies suggest a schizophrenia susceptibility locus on chromosome 22, particularly with microsatellite marker D22S278 (22q12). In addition to some evidence for linkage to schizophrenia in this region, linkage to bipolar disorder using this marker has also been reported. We tested a group of 60 Bipolar I triads and an expanded group of 79 Bipolar I and Bipolar II triads recruited from a Palestinian Arab population for linkage with the D22S278 marker. Significant linkage was observed using the extended transmission disequilibrium test for multiallelic markers (ETDT) for both Bipolar I (P = 0.031) and the expanded group of Bipolar I and Bipolar II (P = 0.041). These weakly positive results are at least consistent with the hypothesis that this region of chromosome 22 might harbor a susceptibility locus for both major psychoses and should be considered for more intensive study. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:836-838, 2000.

Twin studies have yielded contradictory findings about sex differences in genetic influences on the etiology of alcoholism. Studies based on population registers or epidemiological samples have yielded similar estimates of heritability (50-60% of the total variance) for males and females. In contrast, studies of twins identified through treatment settings have found sizeable genetic contributions to alcoholism in males but usually negligible heritabilities for females. We investigated this discrepancy by applying a "simulated" treatment ascertainment strategy to data on alcohol-related disorders collected by structured interviews with a population-based sample of adult twins aged 18-56 years from the Mid-Atlantic Twin Registry. Structural models were used to estimate heritabilities for two definitions of treatment, and these estimates were compared with those obtained from the population-based sample. In males, heritability estimates were similar across sampling methods, but the treatment ascertainment methods yielded higher estimates of common environmental influences. For females, heritability estimates based on a broad definition of treatment were similar to those obtained by using the random ascertainment design. However, estimates based on sampling women who had been in alcohol-treatment programs were (nonsignificantly) lower than those obtained with the other methods. These results provide partial support for the hypothesis that differences in sampling method may account for differences in heritability estimates for alcoholism among studies of female twins. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:754-761, 2000.

Autism is a rare neurodevelopmental disorder with a strong genetic component. Co-occurrence of autism and chromosomal abnormalities is useful to localize candidate regions that may include gene(s) implicated in autism determinism. Several candidate chromosomal regions are known, but association of chromosome 22 abnormalities with autism is unusual. We report a child with autistic syndrome and a de novo 22q13.3 cryptic deletion detected by FISH. Previously described cases with 22q13.3 deletions shared characteristic developmental and speech delay, but autism was not specifically reported. This case emphasizes a new candidate region that may bear a gene involved in autism etiopathogenesis. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:839-844, 2000.

Large pedigrees can pose a problem for GENEHUNTER linkage analysis software. Differences in two-point and multipoint lodscores were observed when comparing GENEHUNTER to other linkage software. Careful consideration must be given when selecting linkage analysis programs. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:781-783, 2000.

Adenosine deaminase (ADA) plays a relevant role in purine metabolism, immune responses, and peptidase activity, which may be altered in some autistic patients. Codominant ADA1 and ADA2 alleles code for ADA1 and ADA2 allozymes, the most frequent protein isoforms in the general population. Individuals carrying one copy of the ADA2 allele display 15 to 20% lower catalytic activity compared to ADA1 homozygotes. Recent preliminary data suggest that ADA2 alleles may be more frequent among autistic patients than healthy controls. The present study was undertaken to replicate these findings in a new case-control study, to test for linkage/association using a family-based design, and to characterize ADA2-carrying patients by serotonin blood levels, peptiduria, and head circumference. ADA2 alleles were significantly more frequent in 91 Caucasian autistic patients of Italian descent than in 152 unaffected controls (17.6% vs. 7.9%, P = 0.018), as well as among their fathers. Family-based tests involving these 91 singleton families, as well as 44 additional Caucasian-American trios, did not support significant linkage/association. However, the observed preferential maternal transmission of ADA2 alleles, if replicated, may point toward linkage disequilibrium between the ADA2 polymorphism and an imprinted gene variant located in its vicinity. Racial and ethnic differences in ADA allelic distributions, together with the low frequency of the ADA2 allele, may pose methodological problems to future linkage/association studies. Direct assessments of ADA catalytic activity in autistic individuals and unaffected siblings carrying ADA1/ADA1 vs ADA1/ADA2 genotypes may provide stronger evidence of ADA2 contributions to autistic disorder. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:784-790, 2000.