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BackgroundAssociations between childhood trauma, neurodevelopment, alcohol use disorder (AUD), and posttraumatic stress disorder (PTSD) are understudied during adolescence.MethodsUsing 1652 participants (51.75% female, baseline Mage = 14.3) from the Collaborative Study of the Genetics of Alcoholism, we employed latent growth curve models to (1) examine associations of childhood physical, sexual, and non-assaultive trauma (CPAT, CSAT, and CNAT) with repeated measures of alpha band EEG coherence (EEGc), and (2) assess whether EEGc trajectories were associated with AUD and PTSD symptoms. Sex-specific models accommodated sex differences in trauma exposure, AUD prevalence, and neural development.ResultsIn females, CSAT was associated with higher mean levels of EEGc in left frontocentral (LFC, ß = 0.13, p = 0.01) and interhemispheric prefrontal (PFI, ß = 0.16, p < 0.01) regions, but diminished growth in LFC (ß = -0.07, p = 0.02) and PFI (ß = -0.07, p = 0.02). In males, CPAT was associated with lower mean levels (ß = -0.17, p = 0.01) and increased growth (ß = 0.11, p = 0.01) of LFC EEGc. Slope of LFC EEGc was inversely associated with AUD symptoms in females (ß = -1.81, p = 0.01). Intercept of right frontocentral and PFI EEGc were associated with AUD symptoms in males, but in opposite directions. Significant associations between EEGc and PTSD symptoms were also observed in trauma-exposed individuals.ConclusionsChildhood assaultive trauma is associated with changes in frontal alpha EEGc and subsequent AUD and PTSD symptoms, though patterns differ by sex and trauma type. EEGc findings may inform emerging treatments for PTSD and AUD.

Abstract Background Age at onset of Huntington's disease (HD) is correlated with the size of the abnormal CAG repeat expansion in the HD gene; however, several studies have indicated that other genetic factors also contribute to the variability in HD age at onset. To identify modifier genes, we recently reported a whole-genome scan in a sample of 629 affected sibling pairs from 295 pedigrees, in which six genomic regions provided suggestive evidence for quantitative trait loci (QTL), modifying age at onset in HD. Methods In order to test the replication of this finding, eighteen microsatellite markers, three from each of the six genomic regions, were genotyped in 102 newly recruited sibling pairs from 69 pedigrees, and data were analyzed, using a multipoint linkage variance component method, in the follow-up sample and the combined sample of 352 pedigrees with 753 sibling pairs. Results Suggestive evidence for linkage at 6q23-24 in the follow-up sample (LOD = 1.87, p = 0.002) increased to genome-wide significance for linkage in the combined sample (LOD = 4.05, p = 0.00001), while suggestive evidence for linkage was observed at 18q22, in both the follow-up sample (LOD = 0.79, p = 0.03) and the combined sample (LOD = 1.78, p = 0.002). Epistatic analysis indicated that there is no interaction between 6q23-24 and other loci. Conclusion In this replication study, linkage for modifier of age at onset in HD was confirmed at 6q23-24. Evidence for linkage was also found at 18q22. The demonstration of statistically significant linkage to a potential modifier locus opens the path to location cloning of a gene capable of altering HD pathogenesis, which could provide a validated target for therapeutic development in the human patient.

Alcoholism is a disease that runs in families and results at least in part from genetic risk factors. The Collaborative Study on the Genetics of Alcoholism (COGA) is a Federally funded effort to identify and characterize those genetic factors. The study involves more than 1,000 alcoholic subjects and their families, with researchers conducting comprehensive psychological, physiological, electrophysiological, and genetic analyses of the participants. These analyses have identified several traits, or phenotypes, that appear to be genetically determined, such as the presence of alcohol dependence, the level of response to alcohol, the presence of coexisting depression, or the maximum number of drinks a person consumes per occasion. Genetic analyses have identified regions on several chromosomes that are associated with these phenotypes and need to be studied further.

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 (GABAA) 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 GABAA receptor genes. Uncovering the genes influencing brain oscillations provides a better understanding of the neural function involved in information processing.

A gene on human chromosome 12 may be linked to late-onset Alzheimer's disease. Researchers used various genetic analyses to screen all chromosomes in 54 families with at least one member who had Alzheimer's disease. Fifteen chromosomes were identified as likely candidates and further analysis revealed that four of these chromosomes, namely 4, 6, 12, and 20, were the most likely candidates. Chromosome 12 in particular was most strongly linked to Alzheimer's disease, especially a region near the centromere. The centromere is a structure close to the midpoint of the chromosome., Context.--Four genetic loci have been identified as contributing to Alzheimer disease (AD), including the amyloid precursor protein gene, the presenilin 1 gene, the presenilin 2 gene, and the apolipoprotein E gene, but do not account for all the genetic risk for AD. Objective.--To identify additional genetic risk factors for late-onset AD. Design.--A complete genomic screen was performed (N=280 markers). Critical values for chromosomal regional follow-up were a P value of .05 or less for affected relative pair analysis or sibpair analysis, a parametric loaf score of 1.0 or greater, or both. Regional follow-up included analysis of additional markers and a second data set. Setting.--Clinic populations in the continental United States. Patients.--From a series of multiplex families affected with late-onset ([is greater than or equal to] 60 years) AD ascertained during the last 14 years (National Insititute of Neurological Disorders and Stroke-Alzheimer&apos;s Disease and Related Disorders Association diagnostic criteria) and for which DNA has been obtained, a subset of 16 families (135 total family members, 52 of whom were patients with AD) was used for the genomic screen. A second subset of 38 families (216 total family members, 89 of whom were patients with AD) was used for the follow-up analysis. Main Outcome Measures.--Linkage analysis results generated using both genetic model-dependent (loaf score) and model-independent methods. Results.--Fifteen chromosomal regions warranted initial follow-up. Follow-up analyses revealed 4 regions of continued interest on chromosomes 4,6,12, and 20, with the strongest results observed for chromosome 12. Peak 2-point affecteds-only loaf scores (n=54) were 1.3, 1.6, 2.7, and 2.2 and affected relative pairs P values (n=54) were .04, .03, .14, and .04 for D12S373, D12S1057, D12S1042, and D12S390, respectively. Sibpair analysis (n=54) resulted in maximum loaf scores (MLSs) of 1.5,2.6,3.2, and 2.3 for these markers, with a peak multipoint MLS of 3.5. A priori stratification by APOEgenotype identified 27 families that had at least 1 member with AD whose genotype did not contain an APOE*4 allele. Analysis of these 27 families resulted in MLSs of 1.0,2.4,3.7, and 3.3 and a peak multipoint MLS of 3.9. Conclusions.--A complete genomic screen in families affected with late-onset AD identified 4 regions of interest after follow-up. Chromosome 12 gave the strongest and most consistent results with a peak multipoint MLS of 3.5, suggesting that this region contains a new susceptibility gene for AD. Additional analyses are necessary to identify the chromosome 12 susceptibility gene for AD and to follow up the regions of interest on chromosomes 4, 6, and 20. JAMA, 1997;278:1237-1241

Amyotrophic lateral sclerosis (ALS; also known as Lou Gehrig's disease) is more common than multiple sclerosis, affecting about five to six people out of every 100,000. The disease is usually deadly within five years, and most sufferers live no longer than three years after the onset of symptoms. Despite much research, the cause for ALS is not known, and no effective treatment has yet been devised. The majority of cases of ALS are sporadic, but a few cases seem to be inherited as a dominant trait within families. Curiously, while male ALS patients outnumber female patients by two to one for the sporadic variety of ALS, men and women seem to be equally affected by the inherited variety. From 10 to 15 percent of all cases of ALS are familial; in the May 16, 1991 issue of The New England Journal of Medicine, researchers have reported the results of a major study to identify the location of the gene for the familial form of ALS. In a study involving 23 families with ALS, the investigators sought out a handful of DNA markers which were usually inherited along with the disease gene as the trait is passed from generation to generation. Their data showed that in many families, the disease gene seems to be located on the long arm of chromosome 21. Unfortunately, some doubt remains, and the interpretation must remain open to question. One of the greatest problems facing this sort of research is that while families might be difficult to seek out, it is even harder to find one with more than a single affected member. In a disease that usually kills within five years, finding affected members in two generations is unlikely indeed. As a result, it is difficult to achieve the kind of reliability which genetic researchers would like. Another finding to arise from this work is that the familial form of ALS may not arise from mutations in only one gene. There is evidence that the disease in some families may result from a mutation in a gene in a totally different location. The researchers could not find any differences in the disease symptoms between the patients that appeared to have their mutation of chromosome 21 and those who had some other mutation. The existence of clinically indistinguishable diseases resulting from the mutation of different genes is not unprecedented, and has been noted in diseases such as familial Alzheimer's disease and polycystic kidney disease. (Consumer Summary produced by Reliance Medical Information, Inc.)