A Developmentally-Informative Genome-wide Association Study of Alcohol Use Frequency.

Contemporary genome-wide association study (GWAS) methods typically do not account for variability in genetic effects throughout development. We applied genomic structural equation modeling to combine developmentally-informative phenotype data and GWAS to create polygenic scores (PGS) for alcohol use frequency that are specific to developmental stage. Longitudinal cohort studies targeted for gene-identification analyses include the Collaborative Study on the Genetics of Alcoholism (adolescence n = 1,118, early adulthood n = 2,762, adulthood n = 5,255), the National Longitudinal Study of Adolescent to Adult Health (adolescence n = 3,089, early adulthood n = 3,993, adulthood n = 5,149), and the Avon Longitudinal Study of Parents and Children (ALSPAC; adolescence n = 5,382, early adulthood n = 3,613). PGS validation analyses were conducted in the COGA sample using an alternate version of the discovery analysis with COGA removed. Results suggest that genetic liability for alcohol use frequency in adolescence may be distinct from genetic liability for alcohol use frequency later in developmental periods. The age-specific PGS predicts an increase of 4 drinking days per year per PGS standard deviation when modeled separately from the common factor PGS in adulthood. The current work was underpowered at all steps of the analysis plan. Though small sample sizes and low statistical power limit the substantive conclusions that can be drawn regarding these research questions, this work provides a foundation for future genetic studies of developmental variability in the genetic underpinnings of alcohol use behaviors and genetically-informed, age-matched phenotype prediction.

Polygenic influences on the behavioral effects of alcohol withdrawal in a mixed-ancestry population from the collaborative study on the genetics of alcoholism (COGA).

Alcohol withdrawal (AW) is a feature of alcohol use disorder that may occur in up to half of individuals with chronic, heavy alcohol consumption whenever alcohol use is abruptly stopped or significantly reduced. To date, few genes have been robustly associated with AW; this may be partly due to most studies defining AW as a binary construct despite the multiple symptoms and their range in severity from mild to severe. The current study examined the effects of genome-wide loci on a factor score for AW in high risk and community family samples in the Collaborative Study for the Genetics of Alcoholism (COGA). In addition, we tested whether differentially expressed genes associated with alcohol withdrawal in model organisms are enriched in human genome-wide association study (GWAS) effects. Analyses employed roughly equal numbers of males and females (mean age 35, standard deviation = 15; total N = 8009) and included individuals from multiple ancestral backgrounds. Genomic data were imputed to the HRC reference panel and underwent strict quality control procedures using Plink2. Analyses controlled for age, sex, and population stratification effects using ancestral principal components. We found support that AW is a polygenic disease (SNP-heritability = 0.08 [95 % CI = 0.01, 0.15; pedigree-based heritability = 0.12 [0.08,0.16]. We identified five single nucleotide variants that met genomewide significance, some of which have previously been associated with alcohol phenotypes. Gene-level analyses suggest a role for COL19A1 in AW; H-MAGMA analyses implicated 12 genes associated with AW. Cross-species enrichment analyses indicated that variation within genes identified in model organism studies explained <1 % of the phenotypic variability in human AW. Notably, the surrounding regulatory regions of model organism genes explained more variance than expected by chance, indicating that these regulatory regions and gene sets may be important for human AW. Lastly, when comparing the overlap in genes identified from the human GWAS and H-MAGMA analyses with the genes identified from the animal studies, there was modest overlap, indicating some convergence between the methods and organisms.

Ectopic expression of Camellia oleifera Abel. gibberellin 20-oxidase gene increased plant height and promoted secondary cell walls deposition in Arabidopsis.

MAIN CONCLUSION: Ectopic expression of Camellia oleifera Abel. gibberellin 20-oxidase 1 caused a taller phenotype, promoted secondary cell wall deposition, leaf enlargement, and early flowering, and reduced chlorophyll and anthocyanin accumulation and seed enlargement phenotype in Arabidopsis. Plant height and secondary cell wall (SCW) deposition are important plant traits. Gibberellins (GAs) play important roles in regulating plant height and SCWs deposition. Gibberellin 20-oxidase (GA20ox) is an important enzyme involved in GA biosynthesis. In the present study, we identified a GA synthesis gene in Camellia oleifera. The total length of the CoGA20ox1 gene sequence was 1146 bp, encoding 381 amino acids. Transgenic plants with CoGA20ox1 had a taller phenotype; a seed enlargement phenotype; promoted SCWs deposition, leaf enlargement, and early flowering; and reduced chlorophyll and anthocyanin accumulation. Genetic analysis showed that the mutant ga20ox1-3 Arabidopsis partially rescued the phenotype of CoGA20ox1 overexpression plants. The results showed that CoGA20ox1 participates in the growth and development of C. oleifera. The morphological changes in CoGA20ox1 overexpressed plants provide a theoretical basis for further exploration of GA biosynthesis and analysis of the molecular mechanism in C. oleifera.

Alcohol use polygenic risk score, social support, and alcohol use among European American and African American adults.

Alcohol use is influenced by genetic and environmental factors. We examined the interactive effects between genome-wide polygenic risk scores for alcohol use (alc-PRS) and social support in relation to alcohol use among European American (EA) and African American (AA) adults across sex and developmental stages (emerging adulthood, young adulthood, and middle adulthood). Data were drawn from 4,011 EA and 1,274 AA adults from the Collaborative Study on the Genetics of Alcoholism who were between ages 18-65 and had ever used alcohol. Participants completed the Semi-Structured Assessment for the Genetics of Alcoholism and provided saliva or blood samples for genotyping. Results indicated that social support from friends, but not family, moderated the association between alc-PRS and alcohol use among EAs and AAs (only in middle adulthood for AAs); alc-PRS was associated with higher levels of alcohol use when friend support was low, but not when friend support was high. Associations were similar across sex but differed across developmental stages. Findings support the important role of social support from friends in buffering genetic risk for alcohol use among EA and AA adults and highlight the need to consider developmental changes in the role of social support in relation to alcohol use.

A Pilot Follow-Up Study of Older Alcohol-Dependent COGA Adults.

BACKGROUND: Alcohol consumption and problems are increasing among older adults, who are at elevated risk for alcohol-related accidents and medical problems. This paper describes a pilot follow-up of older adults with a history of alcohol dependence that was designed to determine the feasibility of conducting a more extensive investigation. METHODS: The sample consisted of previously assessed subjects in the Collaborative Studies on the Genetics of Alcoholism who: (i) were age 50+; (ii) had lifetime DSM-IV AD; and (iii) had DNA available. Individuals were located through family contacts, Internet searches, and death registries. A brief telephone interview assessed demographics, health, and alcohol involvement. RESULTS: Of the total sample (N = 2,174), 36% were contacted, 24% were deceased, and 40% were not yet located. Most (89%) contacted subjects were interviewed, and 99% of them agreed to future evaluation. Thirty percent of interviewed subjects reported abstinence for 10+ years, 56% reported drinking within the past year, and 14% last drank between >1 and 10 years ago. There were no age-related past-year differences in weekly consumption (overall sample mean: 16 drinks), number of drinking weeks (30.8), maximum number of drinks in 24 hours (8.1), or prevalence of weekly risky drinking (19%). Among those who drank within the past 5 years, the 3 most common alcohol-related problems were spending excessive time drinking or recovering (49%), drinking more/longer than intended (35%), and driving while intoxicated (35%); and about a third (32%) received some form of treatment. CONCLUSIONS: Over a 1-year period, we located 60% of individuals last seen an average of 23 years ago. The majority of contacted individuals were interviewed and willing to be evaluated again. Although the proportion of individuals currently drinking diminished with age, subjects exhibited troublesome levels of alcohol consumption and problems. Our findings suggest the importance and feasibility of a more comprehensive follow-up.

Polygenic Risk Score Prediction of Alcohol Dependence Symptoms Across Population-Based and Clinically Ascertained Samples.

BACKGROUND: Despite consistent evidence of the heritability of alcohol use disorders (AUDs), few specific genes with an etiological role have been identified. It is likely that AUDs are highly polygenic; however, the etiological pathways and genetic variants involved may differ between populations. The aim of this study was thus to evaluate whether aggregate genetic risk for AUDs differed between clinically ascertained and population-based epidemiological samples. METHODS: Four independent samples were obtained: 2 from unselected birth cohorts (Avon Longitudinal Study of Parents and Children [ALSPAC], N = 4,304; FinnTwin12 [FT12], N = 1,135) and 2 from families densely affected with AUDs, identified from treatment-seeking patients (Collaborative Study on the Genetics of Alcoholism, N = 2,097; Irish Affected Sib Pair Study of Alcohol Dependence, N = 706). AUD symptoms were assessed with clinical interviews, and participants of European ancestry were genotyped. Genomewide association was conducted separately in each sample, and the resulting association weights were used to create polygenic risk scores in each of the other samples (12 total discovery-validation pairs), and from meta-analyses within sample type. We then tested how well these aggregate genetic scores predicted AUD outcomes within and across sample types. RESULTS: Polygenic scores derived from 1 population-based sample (ALSPAC) significantly predicted AUD symptoms in another population-based sample (FT12), but not in either clinically ascertained sample. Trend-level associations (uncorrected p < 0.05) were found for polygenic score predictions within sample types but no or negative predictions across sample types. Polygenic scores accounted for 0 to 1% of the variance in AUD symptoms. CONCLUSIONS: Though preliminary, these results provide suggestive evidence of differences in the genetic etiology of AUDs based on sample characteristics such as treatment-seeking status, which may index other important clinical or demographic factors that moderate genetic influences. Although the variance accounted for by genomewide polygenic scores remains low, future studies could improve gene identification efforts by amassing very large samples, or reducing genetic heterogeneity by informing analyses with other phenotypic information such as sample characteristics. Multiple complementary approaches may be needed to make progress in gene identification for this complex disorder.

Genetic influences on alcohol use across stages of development: GABRA2 and longitudinal trajectories of drunkenness from adolescence to young adulthood.

Longitudinal analyses allow us to understand how genetic risk unfolds across development, in a way that is not possible with cross-sectional analyses of individuals at different ages. This has received little attention in genetic association analyses. In this study, we test for genetic effects of GABRA2, a gene previously associated with alcohol dependence, on trajectories of drunkenness from age 14 to 25. We use data from 1070 individuals who participated in the prospective sample of the Collaborative Study on the Genetics of Alcoholism, in order to better understand the unfolding of genetic risk across development. Piecewise linear growth models were fit to model the influence of genotype on rate of increase in drunkenness from early adolescence to young adulthood (14-18 years), the change in drunkenness during the transition to adulthood (18-19 years) and the rate of change in drunkenness across young adulthood (≥ 19 years). Variation in GABRA2 was associated with an increase in drunkenness that occurred at the transition between adolescence and adulthood. The genotypic effect was more pronounced in females. These analyses illustrate the importance of longitudinal data to characterize how genetic effects unfold across development. The findings suggest that transitions across important developmental periods may alter the relative importance of genetic effects on patterns of alcohol use. The findings also suggest the importance of considering gender when evaluating genetic effects on drinking patterns in males and females.

Discontinuity in the Electronic Structure and Magnetic Order of ß-Co1+xGa1-x.

The present work reports on the calculated electronic and magnetic structure of the binary Co-Ga system at high Co content. ß-CoGa adopts a simple cubic CsCl type structure. Well-ordered CoGa does not exhibit collective magnetism but is a paramagnetic, metallic compound. Neither Co nor Ga deficiency induces magnetic order; however, ferromagnetism is observed for Co-Ga anti-site disorder. The magnetic moment per cell increases by up to approximately 1.2 µB in the completely disordered body-centered cubic structure. With increasing Co content, Co1+xGa1-x maintains the CsCl type structure and becomes ferromagnetic. Most importantly, a discontinuity of the magnetic order with composition is observed at about 10% excess Co, where a change from a low magnetic moment state to a high moment state is observed. This is accompanied by a change in the electronic structure and transport properties. The discontinuity is forced by the increasing exchange splitting related to the localized moment of the additional Co atoms that replace Ga. Subsequently, the magnetic moment increases continuously up to 2.5 µB for x=0.6. For x≳0.6, the structure changes to a face-centered cubic structure with random site occupation and the magnetic moment further increases. Above the magnetic discontinuity, the Curie temperature increases linearly with the Co content from the onset of ferromagnetism, until it reaches its maximum in pure Co.

A latent class analysis of alcohol and posttraumatic stress symptoms among offspring of parents with and without alcohol use disorder.

The co-occurrence of posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD) is widely known, yet few studies have examined whether and how AUD symptoms co-occur with PTSD symptom clusters of hypervigilance, avoidance/numbing, and re-experiencing. The purpose of this study was to examine potential overlap between AUD and posttraumatic stress symptomatology, and to characterize the resultant latent classes in terms of demographics, drinking behaviors, parental AUD, and specific traumas experienced (physical violence, sexual violence, and non-assaultive trauma). We hypothesized that classes would be differentiated by type and severity of AUD and PTS symptoms. Drawing from a sample of white and Black participants from the Collaborative Study on the Genetics of Alcoholism (COGA), we examined young adults between the ages of 18-35 who had experienced trauma (N = 2478). A series of LCA models based on the type of trauma experienced, posttraumatic stress symptoms and problematic alcohol use were then fitted to the data. A four-class solution provided the best fit, consisting of a low symptom class (N = 1134), moderate alcohol/low PTS severity (N = 623), mild alcohol/high PTS severity (N = 544), and high symptom severity (N = 177). Higher prevalence of sexual assault was associated with membership in high PTS severity classes, and parent AUD was associated with membership in each class, particularly when the mother or both parents had the disorder. Using person-centered methods such as LCA is a commonsense approach to understanding the heterogeneity of symptoms, trauma types, and individual-level characteristics associated with trauma-exposed individuals and comorbid AUD-PTSD, and our study is one of relatively few to empirically ascertain the co-occurrence of alcohol and PTS symptoms in a high-risk family sample.

Trauma Exposure and Post-Traumatic Stress Disorder Among Youth in a High-Risk Family Study: Associations with Maternal and Paternal Alcohol Use Disorder.

This study presents findings regarding the prevalence of trauma exposure and Posttraumatic Stress Disorder (PTSD) based on discrete types of trauma (physical, sexual, witnessed violence, and non-assaultive trauma) among 3404 youth in a family study of Alcohol Use Disorder (AUD). Data from the Collaborative Study on the Genetics of Alcoholism (COGA) were used to examine associations of parent AUD with offspring's childhood trauma exposure, and with lifetime diagnosis of DSM-IV PTSD among White and Black participants aged 12-35. Of 3404 youth, 59.7% had parents affected by AUD and 78% experienced ≤1 traumatic events before age 18. AUD in one or both parents was associated with physical, sexual, and witnessed violence among Whites. Among African Americans, maternal AUD was associated with sexual assault. The lifetime PTSD rate among youth exposed to childhood trauma was 8.6%, and mother-only AUD was significantly associated with lifetime PTSD among participants in both groups. PTSD among youth in this study were somewhat higher (7.9% to 8.83%) than those found in general population studies of the same demographic (5% to 6.8%). Maternal AUD appears to be a salient risk factor for sexual assault before age 18 among Black and development of lifetime PTSD among White youth.

Associations of parental alcohol use disorders and parental separation with offspring initiation of alcohol, cigarette and cannabis use and sexual debut in high-risk families.

BACKGROUND AND AIMS: Parental alcohol use disorders (AUDs) and parental separation are associated with increased risk for early use of alcohol in offspring, but whether they increase risks for early use of other substances and for early sexual debut is under-studied. We focused on associations of parental AUDs and parental separation with substance initiation and sexual debut to (1) test the strength of the associations of parental AUDs and parental separation with time to initiation (age in years) of alcohol, tobacco and cannabis use and sexual debut and (2) compare the strength of association of parental AUD and parental separation with initiation. DESIGN: Prospective adolescent and young adult cohort of a high-risk family study, the Collaborative Study on the Genetics of Alcoholism (COGA). SETTING: Six sites in the United States. PARTICIPANTS: A total of 3257 offspring (aged 14-33 years) first assessed in 2004 and sought for interview approximately every 2 years thereafter; 1945 (59.7%) offspring had a parent with an AUD. MEASUREMENTS: Diagnostic interview data on offspring substance use and sexual debut were based on first report of these experiences. Parental life-time AUD was based on their own self-report when parents were interviewed (1991-2005) for most parents, or on offspring and other family member reports for parents who were not interviewed. Parental separation was based on offspring reports of not living with both biological parents most of the time between ages 12 and 17 years. FINDINGS: Parental AUDs were associated with increased hazards for all outcomes, with cumulative hazards ranging from 1.19 to 2.71. Parental separation was also an independent and consistent predictor of early substance use and sexual debut, with hazards ranging from 1.19 to 2.34. The strength of association of parental separation with substance initiation was equal to that of having two AUD-affected parents, and its association with sexual debut was stronger than the association of parental AUD in one or both parents. CONCLUSIONS: Parental alcohol use disorders (AUDs) and parental separation are independent and consistent predictors of increased risk for early alcohol, tobacco and cannabis use and sexual debut in offspring from families with a high risk of parental AUDs.

Reciprocal relationships between substance use and disorders and suicidal ideation and suicide attempts in the Collaborative Study of the Genetics of Alcoholism.

BACKGROUND: Substance use and misuse and suicidal thoughts and behaviors tend to co-occur. The purpose of this study was to examine whether (a) suicidal ideation and attempt are related to onset of alcohol, nicotine and cannabis use and dependence; (b) early use of alcohol, nicotine and cannabis is associated with onset of suicidal ideation and attempt; and (c) whether these associations persist while controlling for covariates, such as family history of alcohol problems, major depression and other internalizing and externalizing disorders. METHODS: The prospective cohort of the Collaborative Study of the Genetics of Alcoholism (COGA; N=3277) was used. Cross-sectional and discrete time logistic regression (i.e. survival) analyses examined associations between suicidal ideation and attempt and onset of alcohol, nicotine and cannabis use and dependence. Survival models also examined whether individual early substance use was related to onset of ideation and attempt. RESULTS: Ideation was related to 0.71-0.77 odds of onset of subsequent alcohol, nicotine and cannabis use. Attempt was associated with 1.44-1.61 odds of later alcohol, nicotine and cannabis dependence, even after accounting for covariates. Evidence for early substance use being related to subsequent onset of ideation or attempt was limited. Several sex and race differences emerged. LIMITATIONS: The sample was ascertained for family history of alcoholism; not all participants had been followed up allowing for censored observations; reporting bias. CONCLUSION: Suicide attempts are associated with increased likelihood of onset of substance dependence.

Familial association of abstinent remission from alcohol use disorder in first-degree relatives of alcohol-dependent treatment-seeking probands.

BACKGROUND AND AIMS: Studies that have included family history of alcohol use disorder (AUD) as a predictor of remission from AUD have yielded few significant results. The goals of this study were to estimate the association of persistent AUD, non-abstinent remission and abstinent remission ('AUD/remission status') in a proband with AUD/remission status in a relative and to test whether this association differed in related and unrelated proband-relative pairs. DESIGN: High-risk family study of alcohol dependence. Probands were recruited from treatment settings and relatives were invited to participate. Baseline assessments occurred between 1991 and 1998 with follow-up between 1996 and 2005. Half of probands were matched with a biological 1st-degree relative with life-time AUD (related group) and half of probands were paired with an unrelated individual with life-time AUD (unrelated group). SETTING: Brooklyn, New York; Indianapolis, Indiana; Iowa City, Iowa; San Diego, California; Farmington, Connecticut; and St Louis, Missouri, USA. PARTICIPANTS: A total of 606 probands (25.7% female, mean age 37.7) with baseline and follow-up data and 606 of their 1st-degree relatives who had life-ime AUDs (45.8% female, mean age 36.2 years). MEASUREMENTS: Persistent AUD, non-abstinent remission and abstinent remission were based on self-report interview data on most recent AUD symptoms and alcohol consumption. Dependent variable was relatives' AUD/remission status. Independent variable was probands' AUD/remission status. FINDINGS: A total of 34.6% of probands and 20.6% of relatives were abstinent and 11.1% of probands and 22.8% of relatives were in non-abstinent remission. AUD/remission status was correlated significantly in related (r = 0.23, P = 0.0037) but not in unrelated pairs. A significant interaction of probands' abstinent remission with a variable representing related (versus unrelated, P = 0.003) pairs suggested a familial association for abstinent remission. In related pairs, individuals with an abstinent proband were more likely to be abstinent themselves than were individuals whose proband had persistent AUD [relative risk ratio = 3.27, 95% confidence interval (CI) = 1.56-6.85, P = 0.002]; this association was not significant in unrelated pairs. CONCLUSIONS: The likelihood of abstinent remission among people with alcohol use disorder appears to be more than three times greater for individuals who are related to an abstinent proband versus those related to a proband with persistent alcohol use disorder.

A KCNJ6 gene polymorphism modulates theta oscillations during reward processing.

Event related oscillations (EROs) are heritable measures of neurocognitive function that have served as useful phenotype in genetic research. A recent family genome-wide association study (GWAS) by the Collaborative Study on the Genetics of Alcoholism (COGA) found that theta EROs during visual target detection were associated at genome-wide levels with several single nucleotide polymorphisms (SNPs), including a synonymous SNP, rs702859, in the KCNJ6 gene that encodes GIRK2, a G-protein inward rectifying potassium channel that regulates excitability of neuronal networks. The present study examined the effect of the KCNJ6 SNP (rs702859), previously associated with theta ERO to targets in a visual oddball task, on theta EROs during reward processing in a monetary gambling task. The participants were 1601 adolescent and young adult offspring within the age-range of 17-25years (800 males and 801 females) from high-dense alcoholism families as well as control families of the COGA prospective study. Theta ERO power (3.5-7.5Hz, 200-500ms post-stimulus) was compared across genotype groups. ERO theta power at central and parietal regions increased as a function of the minor allele (A) dose in the genotype (AA>AG>GG) in both loss and gain conditions. These findings indicate that variations in the KCNJ6 SNP influence magnitude of theta oscillations at posterior loci during the evaluation of loss and gain, reflecting a genetic influence on neuronal circuits involved in reward-processing. Increased theta power as a function of minor allele dose suggests more efficient cognitive processing in those carrying the minor allele of the KCNJ6 SNPs. Future studies are needed to determine the implications of these genetic effects on posterior theta EROs as possible "protective" factors, or as indices of delays in brain maturation (i.e., lack of frontalization).

Polygenic risk for externalizing disorders: Gene-by-development and gene-by-environment effects in adolescents and young adults.

In this project, we aimed to bring large-scale gene identification findings into a developmental psychopathology framework. Using a family-based sample, we tested whether polygenic scores for externalizing disorders-based on single nucleotide polymorphism weights derived from genome-wide association study results in adults (n = 1,249)-predicted externalizing disorders, subclinical externalizing behavior, and impulsivity-related traits adolescents (n = 248) and young adults (n = 207), and whether parenting and peer factors in adolescence moderated polygenic risk to predict externalizing disorders. Polygenic scores predicted externalizing disorders in adolescents and young adults, even after controlling for parental externalizing disorder history. Polygenic scores also predicted subclinical externalizing behavior and impulsivity traits in the adolescents and young adults. Adolescent parental monitoring and peer substance use moderated polygenic scores to predict externalizing disorders. This illustrates how state of the science genetics can be integrated with psychological science to identify how genetic risk contributes to the development of psychopathology.