Association Analysis and Meta-Analysis of Multi-Allelic Variants for Large-Scale Sequence Data.

There is great interest in understanding the impact of rare variants in human diseases using large sequence datasets. In deep sequence datasets of >10,000 samples, ~10% of the variant sites are observed to be multi-allelic. Many of the multi-allelic variants have been shown to be functional and disease-relevant.

Early Signs of Gut Microbiome Aging: Biomarkers of Inflammation, Metabolism, and Macromolecular Damage in Young Adulthood.

Emerging links between gut microbiota and diseases of aging point to possible shared immune, metabolic, and cellular damage mechanisms, operating long before diseases manifest. We conducted 16S rRNA sequencing of fecal samples collected from a subsample (n = 668) of Add Health Wave V, a nationally representative longitudinal study of adults aged 32-42. An overlapping subsample (n = 345) included whole-blood RNA-seq.

Leveraging genome-wide data to investigate differences between opioid use vs. opioid dependence in 41,176 individuals from the Psychiatric Genomics Consortium.

To provide insights into the biology of opioid dependence (OD) and opioid use (i.e., exposure, OE), we completed a genome-wide analysis comparing 4503 OD cases, 4173 opioid-exposed controls, and 32,500 opioid-unexposed controls, including participants of European and African descent (EUR and AFR, respectively).

Association between the oral microbiome and brain resting state connectivity in smokers.

Recent studies have shown a critical role of the gastrointestinal microbiome in brain and behavior via the complex gut-microbiome-brain axis. However, the influence of the oral microbiome in neurological processes is much less studied, especially in response to the stimuli, such as smoking, within the oral microenvironment. Additionally, given the complex structural and functional networks in brain, our knowledge about the relationship between microbiome and brain function through specific brain circuits is still very limited.

Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use.

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders. They are heritable and etiologically related behaviors that have been resistant to gene discovery efforts. In sample sizes up to 1.

Transancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders.

Liability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest genome-wide association study to date of DSM-IV-diagnosed AD. Genome-wide data on 14,904 individuals with AD and 37,944 controls from 28 case-control and family-based studies were meta-analyzed, stratified by genetic ancestry (European, n = 46,568; African, n = 6,280).

Proper conditional analysis in the presence of missing data: Application to large scale meta-analysis of tobacco use phenotypes.

Meta-analysis of genetic association studies increases sample size and the power for mapping complex traits. Existing methods are mostly developed for datasets without missing values, i.e.

Genetic influences on the human oral microbiome.

Background: The human oral microbiome is formed early in development. Its composition is influenced by environmental factors including diet, substance use, oral health, and overall health and disease. The influence of human genes on the composition and stability of the oral microbiome is still poorly understood.

The Microbiome in Posttraumatic Stress Disorder and Trauma-Exposed Controls: An Exploratory Study.

Objective: Inadequate immunoregulation and elevated inflammation may be risk factors for posttraumatic stress disorder (PTSD), and microbial inputs are important determinants of immunoregulation; however, the association between the gut microbiota and PTSD is unknown. This study investigated the gut microbiome in a South African sample of PTSD-affected individuals and trauma-exposed (TE) controls to identify potential differences in microbial diversity or microbial community structure.

Methods: The Clinician-Administered PTSD Scale for DSM-5 was used to diagnose PTSD according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria.

Test for association of common variants in GRM7 with alcohol consumption.

Recent work using a mouse model has identified the glutamate metabotropic receptor 7 (Grm7) gene as a strong candidate gene for alcohol consumption. Although there has been some work examining the effect of human glutamate metabotropic receptor 7 (GRM7) polymorphisms on human substance use disorders, the majority of the work has focused on other psychiatric disorders such as ADHD, major depressive disorder, schizophrenia, bipolar disorder, panic disorder, and autism spectrum disorders. The current study aimed to evaluate evidence for association between GRM7 and alcohol behaviors in humans using a single nucleotide polymorphism (SNP) approach, as well as a gene-based approach.

Examination of genetic variation in GABRA2 with conduct disorder and alcohol abuse and dependence in a longitudinal study.

Previous studies have shown associations between single nucleotide polymorphisms (SNPs) in gamma aminobutyric acid receptor alpha 2 (GABRA2) and adolescent conduct disorder (CD) and alcohol dependence in adulthood, but not adolescent alcohol dependence. The present study was intended as a replication and extension of this work, focusing on adolescent CD, adolescent alcohol abuse and dependence (AAD), and adult AAD. Family based association tests were run using Hispanics and non-Hispanic European American subjects from two independent longitudinal samples.

Nurture trumps nature in a longitudinal survey of salivary bacterial communities in twins from early adolescence to early adulthood.

Variation in the composition of the human oral microbiome in health and disease has been observed. We have characterized inter- and intra-individual variation of microbial communities of 107 individuals in one of the largest cohorts to date (264 saliva samples), using culture-independent 16S rRNA pyrosequencing. We examined the salivary microbiome in up to three time-points during 10 yr spanning adolescence, and determined the influence of human genotype, gender, age, and weight class.

Association of candidate genes with antisocial drug dependence in adolescents.

The Colorado Center For Antisocial Drug Dependence (CADD) is using several research designs and strategies in its study of the genetic basis for antisocial drug dependence in adolescents. This study reports single nucleotide polymorphism (SNP) association results from a targeted gene assay (SNP chip) of 231 primarily Caucasian male probands in treatment with antisocial drug dependence and a matched set of community controls. The SNP chip was designed to assay 1500 SNPs distributed across 50 candidate genes that have had associations with substance use disorders and conduct disorder.

The human protein kinase C gamma gene (PRKCG) as a susceptibility locus for behavioral disinhibition.

This study explores the association between a highly heritable behavioral disinhibition phenotype and the protein kinase C gamma (PRKCG) gene in an ethnically diverse youth sample from Colorado, USA. The rationale for this study was based on the impulsive behavior and increased ethanol consumption observed in the protein kinase C gamma (PKC-gamma)-deficient mouse model. Two composite behavioral disinhibition phenotypes and their component behavioral scores [conduct disorder, attention-deficit hyperactivity disorder (ADHD), substance experimentation (SUB) and novelty-seeking] were examined for association with five independent PRKCG single nucleotide polymorphisms (SNPs).

Association of the neuronal nicotinic receptor beta2 subunit gene (CHRNB2) with subjective responses to alcohol and nicotine.

Nicotine addiction and alcohol dependence are highly comorbid disorders that are likely to share overlapping genetic components. We have examined two neuronal nicotinic receptor subunit genes (CHRNA4 and CHRNB2) for possible associations with nicotine and alcohol phenotypes, including measures of frequency of use and measures of initial subjective response in the period shortly after first using the drugs. The subjects were 1,068 ethnically diverse young adults participating in ongoing longitudinal studies of adolescent drug behaviors at the University of Colorado, representing both clinical and community samples.

A genome-wide scan for loci influencing adolescent cannabis dependence symptoms: evidence for linkage on chromosomes 3 and 9.

Objective: Cannabis is the most frequently abused illicit substance among adolescents and young adults. Genetic risk factors account for part of the variation in the development of cannabis dependence symptoms; however, no linkage studies have been performed for cannabis dependence symptoms. This study aimed to identify such loci.

Diversity in transcriptional start site selection and alternative splicing affects the 5'-UTR of mouse striated muscle myosin transcripts.

We have analyzed nearly 2,000 myosin heavy chain gene (Myh) clones representing over 30 different transcripts from seven of eight striated muscle Myh genes expressed in mouse. We also report the transcriptional start sites (TSS) for the mouse developmental Myh genes. The data reveal a previously unknown diversity of TSSs and 5'-end alternative splicing in these transcripts.

A genome-wide search for quantitative trait Loci that influence antisocial drug dependence in adolescence.

Background: Among adolescents, externalizing problem behavior and substance use disorders are often comorbid. Familial influences, including shared genetic risk factors, may account for part of this comorbidity. Previously we reported 2 chromosomal regions (3q24-3q25 and 9q34) likely to contain genes that influence substance dependence vulnerability (DV) in adolescence.

Inversion, duplication, and changes in gene context are associated with human chromosome 18 evolution.

Human chromosome 18 differs from its homologues in the great apes by a pericentric inversion. We have identified a chimpanzee bacterial artificial chromosome that spans a region where a break is likely to have occurred in a human progenitor and have characterized the corresponding regions in both chimpanzees and humans. Interspecies sequence comparisons indicate that the ancestral break occurred between the genes ROCK1 and USP14.

A genome-wide search for quantitative trait loci influencing substance dependence vulnerability in adolescence.

This study describes results from a genome-wide search for quantitative trait loci (QTL) influencing substance dependence vulnerability in adolescence. We utilized regression-based multipoint (and single-point) QTL mapping procedures designed for selected sibpair samples. Selected sibling pairs included 250 proband-sibling pairs from 192 families.