Linkage disequilibrium between the beta frequency of the human EEG and a GABAA receptor gene locus

Human brain oscillations represent important features of information processing and are highly heritable. A common feature of beta oscillations (13-28 Hz) is the critical involvement of networks of inhibitory interneurons as pacemakers, gated by gamma-aminobutyric acid type A (GABA(A)) action. Advances in molecular and statistical genetics permit examination of quantitative traits such as the beta frequency of the human electroencephalogram in conjunction with DNA markers. We report a significant linkage and linkage disequilibrium between beta frequency and a set of GABA(A) receptor genes. Uncovering the genes influencing brain oscillations provides a better understanding of the neural function involved in information processing.     

Familial Alzheimer's disease: progress and problems

This paper reexamines recent epidemiologic and molecular genetic studies on the genetic basis of Alzheimer's Disease (AD). Careful analysis of the available epidemiologic data strongly suggests that at least a proportion of AD results from the inheritance of an autosomal dominant gene defect. However, studies of isolated families, of concordance rates in twins, and of risk for AD in relatives of AD probands yield conflicting data. While it is likely that much of the conflict can be ascribed to methodologic differences, it remains premature to conclude that all AD is transmitted as an autosomal dominant trait. Molecular genetic techniques hold the promise of isolation and characterization of the genetic defect(s) in familial AD (FAD). Recently, chromosome 21 has been implicated as the potential site of an autosomal dominant defect in some but not necessarily all FAD pedigrees. However, the results of recent genetic epidemiologic studies suggest that progress in the molecular genetic approach to AD will be difficult.     

Changes in the cytokine regulation of stem cell self-renewal during ontogeny

The last 10 years have seen the development of a quantitative assay that is specific for transplantable totipotent murine hematopoietic cells with durable in vivo blood-forming ability. Recently, this assay has been successfully adapted to allow the detection and enumeration of an analogous population of human hematopoietic stem cells using myelosuppressed immunodeficient (nonobese diabetic/severe-combined immunodeficiency) mice as recipients. Characterization of the cells detected by this assay indicates their close relationship in both mice and humans with cells detected in vitro as long-term culture-initiating cells (LTC-IC). Culture conditions have now been identified that support a significant net expansion of these cells from both species. More detailed analyses of the cytokine requirements for this response indicate that the viability, mitogenesis and maintenance of LTC-IC function by human CD34+ CD38- cells can be independently regulated by exogenous factors. Superimposed on this uncoupling of hematopoietic stem cell "self-renewal" and proliferation control is a change during ontogeny in the particular cytokines that regulate their responses. These findings unite stochastic and deterministic models of hematopoietic stem cell control through the concept of a molecular mechanism that actively blocks stem cell differentiation and must be maintained when these cells are stimulated to divide by exposure to certain types and concentrations of cytokines.     

A genomic scan for habitual smoking in families of alcoholics: common and specific genetic factors in substance dependence

Smoking is a highly heritable, addictive disorder that commonly co-occurs with alcohol dependence. The purpose of this study is to perform a genomic screen for habitual smoking and comorbid habitual smoking and alcohol dependence in families from the Collaborative Study on the Genetics of Alcoholism (COGA). Subjects were assessed using the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) to evaluate alcohol dependence and habitual smoking (smoking one pack per day or more for at least 6 months). Sixty seven multi-generational families with 154 independent sibling pairs affected with habitual smoking were genotyped in a screening sample. Analyses on 79 multi-generational families with 173 independent sibling pairs were repeated in a replication sample. Sibpair analyses were performed using ASPEX. Four chromosomal regions in the screening sample had increased allele sharing among sibling pairs for habitual smoking with a LOD score greater than 1 (chromosomes 5, 9, 11, and 21). The highest LOD score was on chromosome 9 (LOD = 2.02; allele sharing 58.9%). Four chromosomal regions also had modest evidence for linkage to the comorbid phenotype habitual smoking and alcohol dependence (chromosomes 1, 2, 11, 15); and the strongest finding was on chromosome 2 (LOD = 3.30; allele sharing 69.1%). Previously identified areas (chromosomes 1 and 7) implicated in the development of alcohol dependence in this same data set did not provide evidence for linkage to habitual smoking in the screening sample. In the replication data set, there continued to be increased allele sharing near peaks identified in the screening sample on chromosomes 2 and 9, but the results were modest. An area on chromosome 7, approximately 60 cM from a location previously identified in linkage analysis with alcohol dependence, had increased allele sharing for the comorbid habitual smoking and alcohol dependence. These data provide evidence of specific genetic regions involved in the development of habitual smoking and not alcohol dependence. Conversely, genetic regions that influence the development of alcohol dependence do not appear to contribute to the development of habitual smoking. Finally, there is also evidence of an area on chromosome 2 that may reflect a common genetic vulnerability locus to both habitual smoking and alcohol dependence.     

A new mutation in the proteolipid protein (PLP) gene in a German family with pelizaeus-merzbacher disease

A C-to-T transition in exon 4 of the PLP gene was found in 2 affected males and two obligate carriers in a German family with Pelizaeus–Merzbacher disease. The mutation, which causes loss of an HphI site and changes amino acid 155 from threonine to isoleucine, was absent from 108 normal chromosomes. There are 5 concordances and 1 discrepancy between these results and those obtained by magnetic resonance imaging in this family.     

The adducted thumbs syndrome

Four children with similar anomalies inclucling cleft palate, arthrogryposis, craniostenosis, swallowing difficulties, and microcephaly are presented. Three of the four are Amish and trace back to a single pair of common ancestors. Neuropathological studies of one affected infant, who died at 18 days of age, revealed dysmyelination with excessive myelin-dependent gliosis, myelin solubilization, and transient formation of phospholipid-containing plaques on the surface of the central nervous system during formalin fixation.
All four affected individuals had thumbs flexed and adducted across the palms, leacling to the suggestion that "Adducted Thumbs Syndrome" be used to identify this autosomal recessive disease until the basic genetic defect is further characterized.     

Incidence of cleft lip and palate in the offspring of cleft parents

The results of this study support the idea that CL(P) is a polygenic trait. Furthermore, employing the calculations of Edwards, there was little evidence for major gene effects. The sex-modified threshold concept which has been made an integral part of the CL(P) polygenic model was not entirely confirmed by these data.
These data show an affected offspring risk for CP parents of both sexes of about 6 %. Although Edward's calculations failed to provide evidence for major gene effects in CP, there was an unexplained five-fold difference between CP frequency in offspring and sibs which needs further study.     

Initial genomic scan of the NIMH genetics initiative bipolar pedigrees: Chromosomes 3, 5, 15, 16, 17, and 22

As part of the four-center NIMH Genetics Initiative on Bipolar Disorder we carried out a genomic scan of chromosomes 3, 5, 15, 16, 17, and 22. Genotyping was performed on a set of 540 DNAs from 97 families, enriched for affected relative pairs and parents where available. We report here the results of the initial 74 markers that have been typed on this set of DNAs. The average distance between markers (θ) was 12.3 cM. Nonparametric analysis of excess allele sharing among affected sibling pairs used the SIBPAL program of the S.A.G.E. package to test three hierarchical models of affected status. D16S2619 gave some evidence of linkage to bipolar disorder, with P = 0.006 for Model II (in which bipolar 1, bipolar 2 and schizoaffective-bipolar type individuals are considered affected). Nearby markers also showed increased allele sharing. A second interesting region was toward the telomere of chromosome 5q, where D5S1456 and nearby markers showed increased allele sharing; for D5S1456, P = 0.05, 0.015 and 0.008 as the models of affected status become more broad. MOD score analysis also supported the possible presence of a susceptibility locus in this region of chromosome 5. A pair of adjacent markers on chromosome 3, D3S2405 and D3S3038, showed a modest increased allele sharing in the broad model. Several isolated markers had excess allele sharing at the P < 0.05 level under a single model. D15S217 showed a MOD score of 2.37 ( P < 0.025). Multipoint analysis flagged the region of chromosome 22 around D22S533 as the most interesting. Thus, several regions showed modest evidence for linkage to bipolar disorder in this initial genomic scan of these chromosomes, including broad regions near previous reports of possible linkage. Am. J. Med. Genet. 74:238–246, 1997. © Wiley-Liss, Inc.