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Objective: Sequencing cell‐free DNA now allows detection of large chromosomal abnormalities and dominant Mendelian disorders in the prenatal period. Improving upon these methods would allow newborn screening programs to begin with prenatal genetics, ultimately improving the management of rare genetic disorders. Methods: As a pilot study, we performed exome sequencing on the cell‐free DNA from three mothers with singleton pregnancies to assess the viability of broad sequencing modalities in a noninvasive prenatal setting. Results: We found poor resolution of maternal and fetal genotypes due to both sampling and technical issues. Conclusion: We find broad sequencing modalities inefficient for noninvasive prenatal applications. Alternatively, we suggest a more targeted path forward for noninvasive prenatal genotyping. Key points: What's already known about this topic?Sequencing‐based noninvasive testing detects large copy number abnormalities and some single‐gene disorders.Fetal exome sequencing (ES) provides 10%–20% diagnostic yield for structural abnormalities after normal karyotype and microarray. What does this study add?Cell‐free ES in three gravid patients with suspected genetic disease in the fetus.Discussion of probability theory underlying noninvasive fetal genotyping.We demonstrate broad sequencing approaches are limited by sampling and technical difficulties, concluding broad sequencing is currently inappropriate for noninvasive testing. [ABSTRACT FROM AUTHOR]

Alcohol and other substance use disorders (AUD and SUD) are complex diseases that are postulated to have a polygenic inheritance and are often comorbid with other disorders. The comorbidities may arise partially through genetic pleiotropy. Identification of specific gene variants accounting for large parts of the variance in these disorders has yet to be accomplished. We describe a flexible strategy that takes a variant-trait association database and determines if a subset of disease/straits are potentially pleiotropic with the disorder under study. We demonstrate its usage in a study of use disorders in two independent cohorts: alcohol, stimulants, cannabis (CUD), and multi-substance use disorders (MSUD) in American Indians (AI) and AUD and CUD in Mexican Americans (MA). Using a machine learning method with variants in GWAS catalog, we identified 229 to 246 pleiotropic variants for AI and 153 to 160 for MA for each SUD. Inflammation was the most enriched for MSUD and AUD in AIs. Neurological disorder was the most significantly enriched for CUD in both cohorts, and for AUD and stimulants in AIs. Of the select pleiotropic genes shared among substances-cohorts, multiple biological pathways implicated in SUD and other psychiatric disorders were enriched, including neurotrophic factors, immune responses, extracellular matrix, and circadian regulation. Shared pleiotropic genes were significantly up-regulated in brain regions playing important roles in SUD, down-regulated in esophagus mucosa, and differentially regulated in adrenal gland. This study fills a gap for pleiotropy detection in understudied admixed populations and identifies pleiotropic variants that may be potential targets of interest for SUD. [ABSTRACT FROM AUTHOR]

Background and aims: The emergence of negative affective symptoms during the course of alcohol use disorders (AUDs) (e.g. 'dark side' symptoms) has been suggested theoretically; however, the description of their occurrence is limited. This study operationalized two negative affect symptoms and tested the strength of association between these phenotypes and (1) indicators of the clinical course of the severity of AUD, (2) comorbid Axis I psychiatric disorders, suicidal behaviors and trait neuroticism and (3) whether participants reported drinking to relieve the negative affective symptoms. Design A retrospective cross‐sectional study was used to evaluate associations, using logistic regression, between the two negative affective symptoms and clinical measures of AUD severity and progression as well as comorbidity with other psychiatric disorders and conditions, adjusted for demographic characteristics. Setting: US community‐based studies. Participants: A total of 2568 individuals with AUDs obtained from larger population studies that targeted individuals of European American (n = 1663), Mexican American and American Indian (n = 905) ancestry. Measurements Semi‐Structured Assessment for the Genetics of Alcoholism was used to ascertain the two 'dark side' phenotypes, clinical diagnoses, the clinical course of AUD and associated symptoms. The two phenotypes were: (1) being anxious or depressed when trying to cut down or stop drinking and (2) experiencing disabling depression for more than 24 hours while drinking. Findings Both phenotypes were found to be rare in mild and moderate use disorder and highly prevalent in severe AUDs. Having an independent anxiety or affective disorder and elevated scores on trait neuroticism were also associated significantly with the occurrence of both symptoms, as was alcohol 'craving', elevated treatment‐seeking, suicidal behaviors and drinking to relieve the symptoms. Conclusions: Affective symptoms are common in severe alcohol use disorders are associated with a history of independent affective/anxiety disorders, neuroticism and suicidal behaviors; and may promote further heavy drinking. [ABSTRACT FROM AUTHOR]

Recent advances in genome wide sequencing techniques and analytical methods allow for more comprehensive examinations of the genome than microarray-based genome-wide association studies (GWAS). The present report provides the first application of whole genome sequencing (WGS) to identify low frequency variants involved in cannabis dependence across two independent cohorts. The present study used low-coverage whole genome sequence data to conduct set-based association and enrichment analyses of low frequency variation in protein-coding regions as well as regulatory regions in relation to cannabis dependence. Two cohorts were studied: a population-based Native American tribal community consisting of 697 participants nested within large multi-generational pedigrees and a family-based sample of 1832 predominantly European ancestry participants largely nested within nuclear families. Participants in both samples were assessed for Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) lifetime cannabis dependence, with 168 and 241 participants receiving a positive diagnosis in each sample, respectively. Sequence kernel association tests identified one protein-coding region, C1orf110 and one regulatory region in the MEF2B gene that achieved significance in a meta-analysis of both samples. A regulatory region within the PCCB gene, a gene previously associated with schizophrenia, exhibited a suggestive association. Finally, a significant enrichment of regions within or near genes with multiple splice variants or involved in cell adhesion or potassium channel activity were associated with cannabis dependence. This initial study demonstrates the potential utility of low pass whole genome sequencing for identifying genetic variants involved in the etiology of cannabis use disorders. [ABSTRACT FROM AUTHOR]

Background Higher rates of alcohol use disorders ( AUD) have been observed in some Native American populations than other ethnic groups such as European Americans ( EAs) in the United States. Previous studies have shown that variation in the alcohol dehydrogenase ( ADH) genes may affect the risk for development of AUD and that the prevalence of these variants differs depending on the ancestral origins of a population. Methods In this study, we assessed sequencing variants in the ADH genomic region ( ADH1-7) and tested for their associations with AUD phenotypes in 2 independent populations: an American Indian ( AI) community sample and an EA cohort from the San Francisco Family Alcohol Study. Association tests were conducted for both common and rare variants using sequencing data for 2 phenotypes: the number of alcohol-related life events and the count of alcohol dependence drinking symptoms. A regularized regression method was used to select the best set of ADH variants associated with phenotypes. Variance component model was incorporated in all analyses to leverage the admixture and relatedness. Results Two variants near ADH4 and 2 near ADH1C exhibited significant associations with AUD in AIs; no variant was significant in EAs. Common risk variants in AIs were either absent from or much less frequent in EAs. The feature selection method selected mostly distinct yet often colocated subsets of ADH variants to be associated with AUD phenotypes between the 2 cohorts. In the rare-variant analyses, the only association was observed between the whole region and the alcohol-related life events in AIs. Conclusions Our results suggest that ADH variants, both common and rare, are more likely to impact risk for alcohol-related symptomatology in this AI population than in this EA sample, and ADH variants that might affect AUD are likely different but convergent on similar regions between the 2 populations. [ABSTRACT FROM AUTHOR]

Background Psoriasis is a common inflammatory skin disease, whereas schizophrenia is a psychiatric disorder with substantial comorbidity. Although these two disorders manifest with apparently unrelated phenotypes, there is some evidence suggesting that they share common genetic factors. Methods We implemented a genetic analysis incorporating pleiotropy and annotation to genome-wide association summary statistics data for approximately 120 000 psoriasis and schizophrenia samples, as well as whole blood expression quantitative trait loci in 5311 samples. Results We observed a significant pleiotropic effect between psoriasis and schizophrenia ( p = 5.92 × 10−43). We characterized an enrichment of whole blood expression quantitative trait loci in genome-wide association data for psoriasis and schizophrenia ( q1/ q0 > 1.5, p < 10−77) and we revealed that common variants for both diseases were more likely to confer expression quantitative trait loci effects ( q1/ q0 = 4.197, SE = 0.183). Through joint analysis of the associations in the combined psoriasis and schizophrenia data set, we identified a potential susceptibility PTPN1 gene for psoriasis, which may affect the risk of psoriasis through modulation of the function of TYK2 kinase. Conclusions The results of the present study highlight the expression quantitative trait loci enrichment and pleiotropy in psoriasis and schizophrenia, and also suggest a possible key role of the PTPN1 gene in the etiology of psoriasis. [ABSTRACT FROM AUTHOR]

The Multiple Congenital Anomalies-Hypotonia-Seizures Syndrome 1 (MCAHS1) has been described in two families to date. We describe a 2-year-old Mexican American boy with the syndrome and additional manifestations not yet reported as part of the phenotype. The patient presented with severe hypotonia, microphallus and left cryptorchidism, and was later diagnosed with epilepsy and severe cortical visual impairment. He also had supernumerary nipples, pectus excavatum, a short upturned nose, fleshy ear lobes, and a right auricular pit. Massively parallel exome sequencing and analysis revealed two novel compound heterozygous missense (Trp136Gly and Ser859Thr) variants in the PIGN gene. This report extends and further defines the phenotype of this syndrome. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Objectives Body mass index (BMI) is a well-known measure of obesity with a multitude of genetic and non-genetic determinants. Identifying the underlying factors associated with BMI is difficult because of its multifactorial etiology that varies as a function of geoethnic background and socioeconomic setting. Thus, we pursued a study exploring the influence of the degree of Native American admixture on BMI (as well as weight and height individually) in a community sample of Native Americans ( n = 846) while accommodating a variety of socioeconomic and cultural factors. Methods Participants' degree of Native American (NA) ancestry was estimated using a genome-wide panel of markers. The participants also completed an extensive survey of cultural and social identity measures: the Indian Culture Scale (ICS) and the Orthogonal Cultural Identification Scale (OCIS). Multiple linear regression was used to examine the relation between these measures and BMI. Results Our results suggest that BMI is correlated positively with the proportion of NA ancestry. Age was also significantly associated with BMI, while gender and socioeconomic measures (education and income) were not. For the two cultural identity measures, the ICS showed a positive correlation with BMI, while OCIS was not associated with BMI. Conclusions Taken together, these results suggest that genetic and cultural environmental factors, rather than socioeconomic factors, account for a substantial proportion of variation in BMI in this population. Further, significant correlations between degree of NA ancestry and BMI suggest that admixture mapping may be appropriate to identify loci associated with BMI in this population. Am. J. Hum. Biol. 26:347-360, 2014. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Background: Previous linkage studies, including a study of the Native American population described in the present report, have provided evidence for linkage of alcohol dependence and related traits to chromosome 4q near a cluster of alcohol dehydrogenase (ADH) genes, which encode enzymes of alcohol metabolism. Methods: The present study tested for associations between alcohol dependence and related traits and 22 single-nucleotide polymorphisms (SNPs) spanning the 7 ADH genes. Participants included 586 adult men and women recruited from 8 contiguous Native American reservations. A structured interview was used to assess DSM-III-R alcohol dependence criteria as well as a set of severe alcohol misuse symptoms and alcohol withdrawal symptoms. Results: No evidence for association with the alcohol dependence diagnosis was observed, but an SNP in exon 9 of ADH1B (rs2066702; ADH1B*3) and an SNP at the 5′ end of ADH4 (rs3762894) showed significant evidence of association with the presence of withdrawal symptoms ( p = 0.0018 and 0.0012, respectively). Further, a haplotype analysis of these 2 SNPs suggested that the haplotypes containing either of the minor alleles were protective against alcohol withdrawal relative to the ancestral haplotype ( p = 0.000006). Conclusions: These results suggest that variants in the ADH1B and ADH4 genes may be protective against the development of some symptoms associated with alcohol dependence. [ABSTRACT FROM AUTHOR]

We examined gender differences in age of onset, clinical course, and heritability of alcohol dependence in 2,524 adults participating in the University of California San Francisco (UCSF) family study of alcoholism. Men were significantly more likely than women to have initiated regular drinking during adolescence. Onset of regular drinking was not found to be heritable but was found to be significantly associated with a shorter time to onset of alcohol dependence. A high degree of similarity in the sequence of alcohol-related life events was found between men and women, however, men experienced alcohol dependence symptoms at a younger age and women had a more rapid clinical course. Women were found to have a higher heritability estimate for alcohol dependence ( h2= .46) than men ( h2= .32). These findings suggest that environmental factors influencing the initiation of regular drinking rather than genetic factors associated with dependence may in part underlie some of the gender differences seen in the prevalence of alcohol dependence in this population. [ABSTRACT FROM AUTHOR]

Subtyping of substance dependence disorders holds promise for a number of important research areas including phenotyping for genetic studies, characterizing clinical course, and matching treatment and prevention strategies. This study sought to investigate whether a dichotomous construct similar to Babor's Types A/B and Cloninger's Types I/II for alcohol dependence can be identified for cannabis dependence in a Native American sample. In addition, heritability of this construct and its behavior in a genetic linkage analyses were evaluated. Information on cannabis use and dependence symptoms and other psychiatric disorders was obtained using the Semi-Structured Assessment for the Genetics of Alcoholism from a community sample of 606 American Indians. Hierarchical average linkage and K means cluster analysis was used, and a three-cluster solution was found to generate the best separation of variables. Ninety-one per cent of cannabis-dependent participants fell into one of the two subtypes: Type A/I cluster ( n = 114, 56%) and Type B/II cluster ( n = 70, 35%). Heritability (estimated using Sequential Oligogenic Linkage Analysis Routines) was only significant for the Type B/II cluster ( h2 = 0.44, SE = 0.18, P < 0.01). Evidence for linkage was found for the Type B/II cluster (versus no diagnosis) on chromosome 16 [at 139 centimorgans (cM), Log of the Odds (LOD) score = 4.4], and on chromosome 19 (at 74 cM, LOD score = 6.4). Regions of interest for this phenotype (LOD > 1.5) were also located on chromosomes 14, 21, 22. These findings suggest that a Type B/II cannabis dependence phenotype can be identified in this population and that it is in part heritable and linked to areas of the genome identified previously for drug dependence phenotypes in this population as well as in other studies. [ABSTRACT FROM AUTHOR]

Substance abuse and obesity are health disparities that may afflict Native Americans more than some other ethnic groups. One theoretical assumption concerning Native people is that the long history of dependence on foraging and subsistence agriculture may have led to selective enrichment of traits that improve genetic fitness, so called ‘thrifty’ or ‘fat sparing’ genes. We have speculated that this same selective pressure may have enriched for genetic variants that increase the risk for consumption of alcohol and drugs of abuse. Here, we report the results of a genome scan that compared findings for two consumption phenotypes: ‘any drug dependence and/or regular tobacco use’ and body mass index (BMI) in southwest California (SWC) Indian families. Variance component analyses from SOLAR were used to generate log of the odds ratio (LOD) scores. Evidence for linkage was found on chromosome 6 for both the ‘any drug’ (LOD score = 3.3) and BMI (LOD score = 2.3) phenotypes. Bivariate analyses of the two phenotypes revealed a combined LOD score of 4.1 at that location. Additional loci on chromosomes 6, 15, 16 and 21 were found for the ‘any drug’ phenotype, and on chromosomes 8, 16 and 18 for BMI (LOD scores ranged between 1.2 and 2.3). These results provide suggestive evidence for linkage for substance abuse and BMI in this Mission Indian population and, furthermore, provide preliminary data suggesting that ‘consumption phenotypes’ may share some genetic determinants. [ABSTRACT FROM AUTHOR]

Background: In several national surveys, a younger age of onset of first drink and/or regular drinking has been associated with a higher likelihood of the development of alcohol dependence. Some studies have suggested that age at first drink is primarily an environmentally driven variable whereas others suggest that it may be partially mediated by a general vulnerability to exhibit problem behaviors. Although Native Americans, overall, have the highest prevalence of alcohol dependence of any U.S. ethnic group, the relationship of age of onset of intoxication with alcohol dependence in Native American populations is relatively unknown. Methods: Demographic information and DSM-III-R diagnoses were obtained from 525 Southwest California (SWC) Indian adults residing on contiguous reservations. Survival analyses and Cox and logistic regression were used to investigate the relationship between age of onset of first intoxication and the development of alcohol dependence. Heritability of the age of onset of first intoxication was also determined using SOLAR. Results: Age at first intoxication was not found to be heritable in this population. Early onset of intoxication, however, was found to be significantly associated with both a shorter time to onset of alcohol dependence and increased prevalence in this population, even on taking into account several other risk factors including externalizing diagnoses. Conclusions: These data suggest that effective environmental prevention efforts at reducing underage drinking may be an important strategy to lower the prevalence of alcohol dependence in this high-risk population. [ABSTRACT FROM AUTHOR]

Background: The University of California, San Francisco (UCSF) Family Alcoholism Study is a project designed to identify genetic loci that influence susceptibility to alcohol dependence and related phenotypes. Evidence supports a substantial genetic contribution to alcoholism susceptibility. However, the genetic epidemiology of alcoholism is complex, and its clinical manifestation is heterogeneous, making phenotype definition and demonstration of linkage difficult. Despite these challenges, some progress has been made toward identifying genes. Methods: The UCSF Family Alcoholism Study used a small family design, focusing primarily on sibling pairs and parent-child trios for linkage and association studies. Alcoholism-related phenotypes were assessed through interview and self-report questionnaires, with a focus on unidimensional and subphenotypical traits. Data-driven approaches to determining the most promising phenotypes for genetic analysis are being used. Both genome-wide scan and candidate gene approaches were used. Results: The study enrolled 2154 individuals from 970 families from December 1995 through January 2003. Test-retest and interrater reliability for clinical data are very good, and power estimates suggest that this study will have adequate power by linkage analysis to detect loci with moderate effects. Design, methods, and sample demographics of the UCSF Family Study are presented, along with intrafamilial correlations for primary diagnostic phenotypes. Conclusions: Plans for genetic analysis, novel approaches to phenotype refinement, and the implications of ascertainment bias for heritability estimates are discussed. [ABSTRACT FROM AUTHOR]

Endophenotypes are traits that proceed and predict traits of interest. In this special issue, there are a series of papers on genomic analysis of 17 physiologic traits measured by the Minnesota Center for Twin and Family Research that are thought to be endophenotypes for behavioral clinical traits such as addiction and schizophrenia. Because these 17 traits, which can be precisely defined and measured throughout the life of subjects, display variation in normal subjects and are heritable, it is thought that they may be more tractable to genetic dissection. These articles show that these 17 endophenotypes appear to have a similar architecture to the vast majority of traits with complex modes of inheritance. The study identified several genetic loci that play a role in these endophenotypes. It appears that further progress in understanding the genetics of these 17 endophenotypes can be made with an expanded data set. [ABSTRACT FROM AUTHOR]

Amphetamine-type substances are the second most widely used illicit drugs in the United States. There is evidence to suggest that stimulant use (cocaine and methamphetamine) has a heritable component, yet the areas of the genome underlying these use disorders are yet to be identified. This study's aims were to map loci linked to stimulant dependence, heavy use, and craving in an American Indian community at high risk for substance dependence. DSM diagnosis of stimulant dependence, as well as indices of stimulant "craving," and "heavy use," were obtained using the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA). Genotypes were determined for a panel of 791 microsatellite polymorphisms in 381 members of multiplex families using SOLAR. Stimulant dependence, stimulant "craving," and "heavy stimulant use," were all found to be heritable. Analyses of multipoint variance component LOD scores, failed to yield evidence of linkage for stimulant dependence. For the stimulant "craving" phenotype, linkage analysis revealed a locus that had a LOD score of 3.02 on chromosome 15q25.3-26.1 near the nicotinic receptor gene cluster. A LOD score of 2.05 was found at this same site for "heavy stimulant use." Additional loci with LOD scores above 2.00 were found for stimulant "craving" on chromosomes 12p13.33-13.32 and 18q22.3. These results corroborate the importance of "craving" as an important phenotype that is associated with regions on chromosome 12, 15, and 18, that have been highlighted in prior segregation studies in this and other populations for substance dependence-related phenotypes., (Copyright © 2011 Wiley-Liss, Inc.)

Cannabis is the most widely used illicit drug in the United States. There is ample evidence that cannabis use has a heritable component, yet the genes underlying cannabis use disorders are yet to be completely identified. This study's aims were to map susceptibility loci for cannabis use and dependence and two narrower cannabis-related phenotypes of "craving" and "withdrawal" using a family study design. Participants were 2,524 adults participating in the University of California San Francisco (UCSF) Family Alcoholism Study. DSM-IV diagnoses of cannabis dependence, as well as indices of cannabis craving and withdrawal, were obtained using a modified version of the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA). Genotypes were determined for a panel of 791 microsatellite polymorphisms. Multipoint variance component LOD scores were obtained using SOLAR. Genome-wide significance for linkage (LOD > 3.0) was not found for the DSM-IV cannabis dependence diagnosis; however, linkage analyses of cannabis "craving" and the cannabis withdrawal symptom of "nervous, tense, restless, or irritable" revealed five sites with LOD scores over 3.0 on chromosomes 1, 3, 6, 7, and 9. These results identify new regions of the genome associated with cannabis use phenotypes as well as corroborate the importance of several chromosome regions highlighted in previous linkage analyses for other substance dependence phenotypes.

Alcohol dependence is one of the leading causes of morbidity and mortality in Native Americans. Externalizing disorders such as conduct disorder (CD) and antisocial personality disorder (ASPD) have been demonstrated to have significant comorbidity with alcohol dependence in the general population. This study's aims were to: assess the comorbidity of DSM-III-R ASPD and CD with alcohol dependence, to map susceptibility loci for ASPD and CD, and to see if there is overlap with loci previously mapped for alcohol dependence phenotypes in 587 American Indians. Alcohol dependence was found to be comorbid with DSM-III-R ASPD but not CD. However, the amount of alcohol dependence in the population attributable to ASPD and/or CD is low. ASPD and the combined phenotype of participants with ASPD or CD were both found to have significant heritability, whereas no significant evidence was found for CD alone. Genotypes were determined for a panel of 791 micro-satellite polymorphisms in 251 of the participants. Analyses of multipoint variance component LOD scores, for ASPD and ASPD/CD, revealed six locations that had a LOD score of 2.0 or above: on chromosome 13 for ASPD and on chromosomes 1, 3, 4, 14, 17, and 20 for ASPD/CD. These results corroborate the importance of several chromosomal regions highlighted in prior segregation studies for externalizing diagnoses. These results also further identify new regions of the genome, that do not overlap with alcohol dependence phenotypes previously identified in this population, that may be unique to either the phenotypes evaluated or this population of American Indians., (2008 Wiley-Liss, Inc.)

Genome-wide model free linkage analysis was conducted for nicotine dependence and tobacco use phenotypes in 607 members of 158 nuclear families consisting of at least two ever smokers (100 or more cigarettes smoked in lifetime). DNA from whole blood was genotyped for 739 autosomal microsatellite polymorphisms with an average inter-marker distance of 4.6 cM. A peak LOD score of 2.7 was observed on chromosome 6 for scores for the Fagerström Test for Nicotine Dependence. Exploratory analyses were conducted to determine whether sequence variation at other loci affected other measures of dependence or tobacco use. Four additional loci with LOD scores of 2.7 or more were associated with alternative measures of nicotine dependence, one with current frequency of use, and one with smoking cessation. Several of the corresponding support intervals were near putative loci reported previously (on chromosomes 6, 7, and 8) while others appear to be novel (on chromosomes 5, 16, and 19).

Background: Alcohol consumption and alcoholism are heritable traits. Previous linkage analyses for alcoholism and related traits have identified several putative susceptibility loci. In this paper we use, for the first time, linkage analysis to search for alcoholism-related phenotypes in a family sample selected for smoking behavior., Methods: Genome-wide model free linkage analysis was conducted for a variety of phenotypes related to alcohol consumption in 158 nuclear families ascertained for having at least two first-degree relatives who smoked 100 or more cigarettes in their lifetime. The phenotypes included dichotomous, ordinal, and continuous traits. Because the traits were typically not normally distributed the QTL score statistic as implemented in Merlin was employed to deal with deviations from normality. Simulation analysis determined that the QTL score statistic is robust to deviations from normality., Results: Linkage analysis detected three loci, one on chromosome 2 and two on chromosome 4, with nominal significance (LOD score > 2.7). These loci appear to be in close proximity to loci reported in other studies., Conclusions: While these findings did not reach genome-wide significance (LOD >4.0 given multiple comparisons) we have confidence that genes in these regions affect alcohol consumption. Two of the three significant findings in this analysis have been reported previously as alcoholism susceptibility loci. Simulation analysis shows that the most widely replicated finding on chromosome 4 is strongly supported (p=0.01) even with correction for multiple comparisons. These findings suggest that previously reported linkage results are robust to the effects of different approaches to sample ascertainment and definition.

Alcohol dependence is a leading cause of morbidity and mortality in Native Americans, yet biological factors underlying the disorder in this ethnic group remain elusive. This study's aims were to map susceptibility loci for DSM-III-R alcohol dependence and two narrower alcohol-related phenotypes in Mission Indian families. Each participant gave a blood sample and completed an interview using the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) that was used to make alcohol dependence diagnoses and the narrower phenotypes of withdrawal, and drinking severity. Genotypes were determined for a panel 791 microsatellite polymorphisms. Analyses of multipoint variance component LOD scores for the dichotomous DSM-III-R phenotype revealed no peak LOD scores that exceeded 2.0 at any chromosome location. Two chromosomes, 4 and 12, had peak LOD scores that exceeded 2 for the alcohol use severity phenotype and three chromosomes 6, 15, 16 were found to have peaks with LOD scores that exceeded 2 for the withdrawal phenotype. Evidence for linkage to chromosomes 4 and 15, and 16 have been reported previously for alcohol related phenotypes whereas no evidence has as yet been reported for chromosomes 6 and 12. Combined linkage and association analysis suggest that alcohol dehydrogenase 1B gene polymorphisms are partially responsible for the linkage result on chromosome 4 in this population. These results corroborate the importance of several chromosomal regions highlighted in prior segregation studies in alcoholism and further identify new regions of the genome that may be unique to either the restricted phenotypes evaluated or this population of Mission Indians., (Copyright 2004 Wiley-Liss, Inc.)

We describe eight members from two large Amish kindreds who share a phenotype characterized by early-onset pigmentary retinopathy and myopia, global developmental delay and mental retardation, microcephaly, short stature, hypotonia, joint hyperextensibility, small hands and feet, common facial appearance, and friendly disposition. Several of the children had intermittent granulocytopenia. The phenotypic occurrence in three siblings coupled with the increased coefficient of inbreeding in the Amish suggested that this disorder is autosomal recessive and due to a single founder allele. Despite similarity to the clinical features of Cohen syndrome, experienced dysmorphologists attending the 23rd David W. Smith Workshop suggested the facial gestalt of the Amish children was inconsistent with this diagnosis. We mapped the locus responsible for these individuals' phenotype to chromosome 8q22-q23, which contains the recently discovered Cohen syndrome gene, COH1. Complete sequencing of the COH1 gene identified a likely disease-causing frameshift mutation and a missense mutation in the Amish patients. A comparison of features among different Cohen syndrome populations with shared linkage to the COH1 locus or known COH1 gene mutations may allow for the determination of improved clinical criteria on which to suspect the diagnosis of Cohen syndrome. We conclude that facial gestalt seems to be an unreliable indicator of Cohen syndrome between ethnic populations, although it is quite consistent among affected individuals within a particular ethnic group. Other features common to almost all individuals with proven COH1 mutations, such as retinal dystrophy, myopia, microcephaly, mental retardation, global developmental delay, hypotonia, and joint hyperextensibility appear to be better clinical indicators of this disorder., (Copyright 2004 Wiley-Liss, Inc.)

Background: Recruiting a large number of participants meeting strict inclusion criteria can be challenging, particularly when selecting for a condition associated with a social stigma such as alcoholism, when participation involves collection of medical specimens and sensitive information, and when the participation of family members or other collaterals is required. Developing and implementing a successful recruitment plan depends upon identifying the most effective recruitment strategies given the available resources., Methods: Several strategies for recruiting subjects for a large family study on the genetics of alcoholism were evaluated over a two-year period with regard to participant yield, time and cost expenditure., Results: Overall effectiveness of a recruitment strategy was determined based on a composite of yield, cost and time expenditure. The most effective recruitment strategies were direct mail, press release, the Internet and treatment center collaborations., Conclusion: Results provide insight into successful strategies for recruiting large numbers of participants and their family members selected for a condition associated with a social stigma.

Background: A low level of response (LR) to alcohol seems to relate to a substantial proportion of the risk for alcoholism and to have significant heritability., Methods: This report describes the results of a genome-wide segregation analysis for the first 139 pairs of full siblings by using an alcohol challenge protocol as a direct measure of LR. Subjects from 18 to 29 years old were selected if the original screen indicated they had an alcohol-dependent parent, reported a personal history of drinking but had no evidence of alcohol dependence, and had a full sibling with similar characteristics. Body sway and Subjective High Assessment Scale scores were measured at baseline and at regular intervals after the administration of a measured dose of alcohol. Participants and available parents were genotyped for 811 microsatellite markers, and resulting data were analyzed with a variance component method., Results: Nine chromosome regions with logarithm of the odds ratio (LOD) between 2.2 and 3.2 were identified; several had previously been implicated regarding phenotypes relevant to alcoholism and the LR to alcohol. Several regions identified in the previous linkage study by using a retrospective self-report questionnaire were potentially confirmed by this study. The strongest evidence was on chromosomes 10, 11, and 22., Conclusions: Several chromosomal areas seem to relate to the low LR to alcohol as a risk factor for alcohol dependence.