Marc A. Schuckit

Genome-wide association study of comorbid depressive syndrome and alcohol dependence

Objective Depression and alcohol dependence (AD) are common psychiatric disorders that often co-occur. Both disorders are genetically influenced, with heritability estimates in the range of 35–60%. In addition, evidence from twin studies suggests that AD and depression are genetically correlated. Herein, we report results from a genome-wide association study of a comorbid phenotype, in which cases meet the Diagnostic and Statistical Manual of Mental Disorders-IV symptom threshold for major depressive symptomatology and the Diagnostic and Statistical Manual of Mental Disorders-IV criteria for AD. Methods Samples (N=467 cases and N=407 controls) were of European-American descent and were genotyped using the Illumina Human 1M BeadChip array. Results Although no single-nucleotide polymorphism (SNP) meets genome-wide significance criteria, we identified 10 markers with P values less than 1×10−5, seven of which are located in known genes, which have not been previously implicated in either disorder. Genes harboring SNPs yielding P values less than 1×10−3 are functionally enriched for a number of gene ontology categories, notably several related to glutamatergic function. Investigation of expression localization using online resources suggests that these genes are expressed across a variety of tissues, including behaviorally relevant brain regions. Genes that have been previously associated with depression, AD, or other addiction-related phenotypes – such as CDH13, CSMD2, GRID1, and HTR1B – were implicated by nominally significant SNPs. Finally, the degree of overlap of significant SNPs between a comorbid phenotype and an AD-only phenotype is modest. Conclusion These results underscore the complex genomic influences on psychiatric phenotypes and suggest that a comorbid phenotype is partially influenced by genetic variants that do not affect AD alone.

Family history and half-sibling research in alcoholism.

Family investigations dating back to the turn of the century have consistently revealed a high familial incidence of alcoholism. Amark2 found that the relatives of alcoholics were frequently ill with alcoholism, psychopathy, and psychogenic psychosis (an illness with a depressive overlay) but only rarely exhibited schizophrenia, general paresis, senile or presenile psychosis, epilepsy, oligophrenia, or (bipolar) manic-depressive illness. His findings indicate alcoholism is a familial illness often found in conjuction with psychopathy and depressive illness. A close association between alcoholism and affective disorder has also been a consistent finding in the Washington University studies. In 1965, Winokur and Pith3 found five times the normal incidence of alcoholism in the fathers of 366 depressed patients. In 1966, the same authors studied the families of 62 alcoholics and found increased incidences of alcoholism in fathers and brothers and increased affective disorder in sisters.4 Winokur and Clayton, in 1968, compared clinical and family factors in 69 male and 45 female alcoholics and noted that both male and female probands showed depression and suicidal thoughts5 In 1970, Winokur and colleagues presented the largest family study of alcoholics to come from Washington University.s Family interviews were done on 259 hospitalized alcoholics from both a state and a private hospital in St. Louis. The diagnosis of alcoholism depended on the presence of any one of the following occurring in relation to alcohol abuse: job loss; a marital separation or divorce; three or more nontraffic arrests or a hospitalization, other than the index admission, directly related to health problems from drinking (e.g. cirrhosis). The same systematic interview for family incidence of psychiatric illness was presented to probands and all available first-degree family members. The frequencies of illness in the family members were analyzed for men and women separately. Data were available on all first-degree relatives, but the most reliable information concerned the 259 probands and the 507 personally interviewed relatives. TABLE 1 shows the morbid risks for alcoholism and affective disorder for the interviewed relatives. The Table shows an incidence of alcoholism in all male first-degree relatives that approaches 50%. Alcoholism in female first-degree relatives was seen only

A systematic study of psychiatric illness in freshman college students.

Abstract The majority of estimates of the rate of college student psychiatric illness has been based on data obtained from treated samples of students. 1,2 The biases inherent in treated samples have been extensively documented. Few studies have dealt with the occurrence of psychiatric illness in a randomly selected sample of students, a study design that avoids the problems of using a treated population. This study describes the psychiatric problems, during the freshman year, of such a randomly selected, prospectively studied sample of 158 college students. The questions to be answered by this report are: (1) What proportion of a college population have a psychiatric problem during the course of the freshman year? (2) What proportion will seek treatment? (3) What proportion of the ill group will seek treatment? (4) What is the predominant psychiatric disturbance seen?

A bootstrapped commingling analysis of platelet monoamine oxidase activity levels corrected for cigarette smoking

Monoamine oxidase (MAO) activity levels have been suggested as a possible biological marker for alcohol dependence and abuse, as well as for schizophrenia and other psychiatric conditions. Using platelet MAO activities in the Collaborative Study on the Genetics of Alcoholism data set, we applied bootstrapping methods as a novel way to test for admixture in families. This bootstrapping involved resampling in family units and hypothesis testing of the resampled datasets for commingling in the distribution of MAO activity levels. Prior to commingling analysis, we used linear models to find covariates of greatest effect on MAO activity levels. While an alcoholism diagnosis was significant in men (n = 1151, P < 0.0001) and women (n = 1254, P = 0.0003), the effect lost significance after controlling for cigarette smoking, indicating alcoholism and smoking behavior to be highly confounded. When smoking histories were compared, former smokers had levels (mean = 7.1) closer to those who never smoked (mean = 7.0) than to current smokers (mean = 5.4). Furthermore, current daily smoking and time since smoking cessation were significantly related to MAO levels, indicating smoking probably has a direct effect on MAO levels, rather than the reverse. These results suggest that studies using MAO levels as a biological marker should consider smoking as an important covariate. Finally, admixture was found in MAO levels controlled for smoking and sex, possibly indicating a major genetic locus; this confirms previous evidence for admixture.

Positive selection on loci associated with drug and alcohol dependence

Much of the evolution of human behavior remains a mystery, including how certain disadvantageous behaviors are so prevalent. Nicotine addiction is one such phenotype. Several loci have been implicated in nicotine related phenotypes including the nicotinic receptor gene clusters (CHRNs) on chromosomes 8 and 15. Here we use 1000 Genomes sequence data from 3 populations (Africans, Asians and Europeans) to examine whether natural selection has occurred at these loci. We used Tajima’s D and the integrated haplotype score (iHS) to test for evidence of natural selection. Our results provide evidence for strong selection in the nicotinic receptor gene cluster on chromosome 8, previously found to be significantly associated with both nicotine and cocaine dependence, as well as evidence selection acting on the region containing the CHRNA5 nicotinic receptor gene on chromosome 15, that is genome wide significant for risk for nicotine dependence. To examine the possibility that this selection is related to memory and learning, we utilized genetic data from the Collaborative Studies on the Genetics of Alcoholism (COGA) to test variants within these regions with three tests of memory and learning, the Wechsler Adult Intelligence Scale (WAIS) Block Design, WAIS Digit Symbol and WAIS Information tests. Of the 17 SNPs genotyped in COGA in this region, we find one significantly associated with WAIS digit symbol test results. This test captures aspects of reaction time and memory, suggesting that a phenotype relating to memory and learning may have been the driving force behind selection at these loci. This study could begin to explain why these seemingly deleterious SNPs are present at their current frequencies.

A systematic study of the prevalence of drug use in freshman college students

Abstract Prior studies of drug use among college student have utilized samples of students attending student health facilities, or a proportion of students responding to mailed or personal questionnaires. 1,2 Both types of samples represent limited and possibly biased sources of information. To overcome this possible bias, the present work reports student drug use in a randomly selected sample of a total student freshman population, with information obtained from 97% of the selected sample of 158 students. The study seeks to ascertain what proportion of students use drugs, how often, which drugs, what changes in student drug use occur during the freshman year, and in what ways users differ from nonusers.