Using genetic information from candidate gene and genome-wide association studies in risk prediction for alcohol dependence

Family-based and genome-wide association studies (GWAS) of alcohol dependence (AD) have reported numerous associated variants. The clinical validity of these variants for predicting AD compared with family history information has not been reported. Using the Collaborative Study on the Genetics of Alcoholism (COGA) and the Study of Addiction: Genes and Environment (SAGE) GWAS samples, we examined the aggregate impact of multiple single nucleotide polymorphisms (SNPs) on risk prediction. We created genetic sum scores by adding risk alleles associated in discovery samples, and then tested the scores for their ability to discriminate between cases and controls in validation samples. Genetic sum scores were assessed separately for SNPs associated with AD in candidate gene studies and SNPs from GWAS analyses that met varying P-value thresholds. Candidate gene sum scores did not exhibit significant predictive accuracy. Family history was a better classifier of case-control status, with a significant area under the receiver operating characteristic curve (AUC) of 0.686 in COGA and 0.614 in SAGE. SNPs that met less stringent P-value thresholds of 0.01-0.50 in GWAS analyses yielded significant AUC estimates, ranging from mean estimates of 0.549 for SNPs with P < 0.01 to 0.565 for SNPs with P < 0.50. This study suggests that SNPs currently have limited clinical utility, but there is potential for enhanced predictive ability with better understanding of the large number of variants that might contribute to risk

Examination of the association of sex and race/ethnicity with appearance concerns: A Scleroderma Patient-centered Intervention Network (SPIN) cohort study

Objective: Appearance concerns are common in systemic sclerosis (SSc) and have been linked to younger age and more severe disease. No study has examined their association with sex or race/ethnicity. Methods: SSc patients were sampled from the Scleroderma Patient-centered Intervention Network Cohort. Presence of appearance concerns was assessed with a single item, and medical and sociodemographic information were collected. Results: Of 644 patients, appearance concerns were present in 72%, including 421 of 565 women (75%), 42 of 79 men (53%), 392 of 550 patients who identified as White (71%), 35 of 41 who identified as Black (85%), and 36 of 53 who identified as another race/ethnicity (68%). In multivariate analysis, women had significantly greater odds of reporting appearance concerns than men (odds ratio (OR)=2.97, 95% confidence interval (CI)=1.78-4.95,

An ADH1B variant and peer drinking in progression to adolescent drinking milestones: Evidence of a gene-by-environment interaction

BACKGROUND: Adolescent drinking is an important public health concern, one that is influenced by both genetic and environmental factors. The functional variant rs1229984 in alcohol dehydrogenase 1B (ADH1B) has been associated at a genome-wide level with alcohol use disorders in diverse adult populations. However, few data are available regarding whether this variant influences early drinking behaviors and whether social context moderates this effect. This study examines the interplay between rs1229984 and peer drinking in the development of adolescent drinking milestones. METHODS: One thousand five hundred and fifty European and African American individuals who had a full drink of alcohol before age 18 were selected from a longitudinal study of youth as part of the Collaborative Study on the Genetics of Alcoholism (COGA). Cox proportional hazards regression, with G × E product terms in the final models, was used to study 2 primary outcomes during adolescence: age of first intoxication and age of first DSM-5 alcohol use disorder symptom. RESULTS: The minor A allele of rs1229984 was associated with a protective effect for first intoxication (HR = 0.56, 95% CI 0.41 to 0.76) and first DSM-5 symptom (HR = 0.45, 95% CI 0.26 to 0.77) in the final models. Reporting that most or all best friends drink was associated with a hazardous effect for first intoxication (HR = 1.81, 95% CI 1.62 to 2.01) and first DSM-5 symptom (HR = 2.17, 95% 1.88 to 2.50) in the final models. Furthermore, there was a significant G × E interaction for first intoxication (p = 0.002) and first DSM-5 symptom (p = 0.01). Among individuals reporting none or few best friends drinking, the ADH1B variant had a protective effect for adolescent drinking milestones, but for those reporting most or all best friends drinking, this effect was greatly reduced. CONCLUSIONS: Our results suggest that the risk factor of best friends drinking attenuates the protective effect of a well-established ADH1B variant for 2 adolescent drinking behaviors. These findings illustrate the interplay between genetic and environmental factors in the development of drinking milestones during adolescence

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 disorders1. They are heritable2,3 and etiologically related4,5 behaviors that have been resistant to gene discovery efforts6-11. In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures

CYP2A6 metabolism in the development of smoking behaviors in young adults

Cytochrome P450 2A6 (CYP2A6) encodes the enzyme responsible for the majority of nicotine metabolism. Previous studies support that slow metabolizers smoke fewer cigarettes once nicotine dependent but provide conflicting results on the role of CYP2A6 in the development of dependence. By focusing on the critical period of young adulthood, this study examines the relationship of CYP2A6 variation and smoking milestones. A total of 1209 European American young adults enrolled in the Collaborative Study on the Genetics of Alcoholism were genotyped for CYP2A6 variants to calculate a previously well-validated metric that estimates nicotine metabolism. This metric was not associated with the transition from never smoking to smoking initiation nor with the transition from initiation to daily smoking (P > 0.4). But among young adults who had become daily smokers (n = 506), decreased metabolism was associated with increased risk of nicotine dependence (P = 0.03) (defined as Fagerström Test for Nicotine Dependence score ≥4). This finding was replicated in the Collaborative Genetic Study of Nicotine Dependence with 335 young adult daily smokers (P = 0.02). Secondary meta-analysis indicated that slow metabolizers had a 53 percent increased odds (OR = 1.53, 95 percent CI 1.11-2.11, P = 0.009) of developing nicotine dependence compared with normal metabolizers. Furthermore, secondary analyses examining four-level response of time to first cigarette after waking (>60, 31-60, 6-30, ≤5 minutes) demonstrated a robust effect of the metabolism metric in Collaborative Study on the Genetics of Alcoholism (P = 0.03) and Collaborative Genetic Study of Nicotine Dependence (P = 0.004), illustrating the important role of this measure of dependence. These findings highlight the complex role of CYP2A6 variation across different developmental stages of smoking behaviors

Reconsidering the Heritability of Intelligence in Adulthood: Taking Assortative Mating and Cultural Transmission into Account

Heritability estimates of general intelligence in adulthood generally range from 75 to 85%, with all heritability due to additive genetic influences, while genetic dominance and shared environmental factors are absent, or too small to be detected. These estimates are derived from studies based on the classical twin design and are based on the assumption of random mating. Yet, considerable positive assortative mating has been reported for general intelligence. Unmodeled assortative mating may lead to biased estimates of the relative magnitude of genetic and environmental factors. To investigate the effects of assortative mating on the estimates of the variance components of intelligence, we employed an extended twin-family design. Psychometric IQ data were available for adult monozygotic and dizygotic twins, their siblings, the partners of the twins and siblings, and either the parents or the adult offspring of the twins and siblings (N = 1314). Two underlying processes of assortment were considered: phenotypic assortment and social homogamy. The phenotypic assortment model was slightly preferred over the social homogamy model, suggesting that assortment for intelligence is mostly due to a selection of mates on similarity in intelligence. Under the preferred phenotypic assortment model, the variance of intelligence in adulthood was not only due to non-shared environmental (18%) and additive genetic factors (44%) but also to non-additive genetic factors (27%) and phenotypic assortment (11%).This non-additive nature of genetic influences on intelligence needs to be accommodated in future GWAS studies for intelligence

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

A Dopaminergic Gene Cluster in the Prefrontal Cortex Predicts Performance Indicative of General Intelligence in Genetically Heterogeneous Mice

Background: Genetically heterogeneous mice express a trait that is qualitatively and psychometrically analogous to general intelligence in humans, and as in humans, this trait co-varies with the processing efficacy of working memory (including its dependence on selective attention). Dopamine signaling in the prefrontal cortex (PFC) has been established to play a critical role in animals ’ performance in both working memory and selective attention tasks. Owing to this role of the PFC in the regulation of working memory, here we compared PFC gene expression profiles of 60 genetically diverse CD-1 mice that exhibited a wide range of general learning abilities (i.e., aggregate performance across five diverse learning tasks). Methodology/Principal Findings: Animals ’ general cognitive abilities were first determined based on their aggregate performance across a battery of five diverse learning tasks. With a procedure designed to minimize false positive identifications, analysis of gene expression microarrays (comprised of &lt;25,000 genes) identified a small number (,20) of genes that were differentially expressed across animals that exhibited fast and slow aggregate learning abilities. Of these genes, one functional cluster was identified, and this cluster (Darpp-32, Drd1a, and Rgs9) is an established modulator of dopamine signaling. Subsequent quantitative PCR found that expression of these dopaminegic genes plus one vascular gene (Nudt6) were significantly correlated with individual animal’s general cognitive performance. Conclusions/Significance: These results indicate that D1-mediated dopamine signaling in the PFC, possibly through it

Resilience to Disturbance Despite Limited Dispersal and Self-Recruitment in Tropical Barrel Sponges: Implications for Conservation and Management

While estimates of connectivity are important for effective management, few such estimates are available for reef invertebrates other than for corals. Barrel sponges are one of the largest and most conspicuous members of the coral reef fauna across the Indo-Pacific and given their large size, longevity and ability to process large volumes of water, they have a major role in reef functioning. Here we used a panel of microsatellite markers to characterise the genetic structure of two barrel sponge species, Xestospongia testudinaria and a currently undescribed Xestospongia species. We sampled across seven populations in the Wakatobi Marine National Park, SE Sulawesi (Indonesia) spanning a spatial scale of approximately 2 to 70 km, and present the first estimates of demographic connectivity for coral reef sponges. Genetic analyses showed high levels of genetic differentiation between all populations for both species, but contrasting patterns of genetic structuring for the two species. Autocorrelation analyses showed the likely dispersal distances of both species to be in the order of 60 and 140 m for Xestopongia sp. and Xestospongia testudinaria, respectively, which was supported by assignment tests that showed high levels of self-recruitment (>80%). We also found consistently high inbreeding coefficients across all populations for both species. Our study highlights the potential susceptibility of barrel sponges to environmental perturbations because they are generally long-lived, slow growing, have small population sizes and are likely to be reliant on self-recruitment. Surprisingly, despite these features we actually found the highest abundance of both barrel sponge species (although they were generally smaller) at a site that has been severely impacted by humans over the last fifty years. This suggests that barrel sponges exhibit environmental adaptation to declining environmental quality and has important implications for the management and conservation of these important reef species. © 2014 Bell et al