Jeanne E. Savage

A Genetically Informed Study of the Longitudinal Relation Between Irritability and Anxious/Depressed Symptoms

OBJECTIVE Little is known about the longitudinal genetic and environmental association between juvenile irritability and symptoms of anxiety and depression. This studys goal was to assess the relationship between these constructs across a critical developmental period spanning childhood to young adulthood. METHOD Parents (n = 1,348 twin pairs) from the Swedish Twin Study of Child and Adolescent Development completed the Child/Adult Behavior Checklist (CBCL/ABCL) about their twin children. Data were collected during a prospective, 4-wave study starting in childhood (ages 8-9 years) and ending in young adulthood (ages 19-20 years). An irritability score and an anxious/depressed score were computed from CBCL/ABCL item endorsements. Genetically informative cross-lagged models were used to estimate the genetic and environmental relationship between these 2 constructs across time. RESULTS Our models suggested that irritability more strongly predicted anxious/depressed symptoms than vice versa, consistent with a causal role of irritability on anxiety/depression at older ages. This relationship was significant only in late childhood/early adolescence. Additive genetic and unique environmental factors were significant contributors to both irritability and anxious/depressed symptoms and were both specific to and shared between these 2 constructs. The same common environmental factors influenced both constructs, although these factors accounted for a smaller amount of variance than genetic or unique environmental factors. CONCLUSION This study adds to our understanding of the developmental relationship between irritability and anxious/depressed symptoms and the contribution of genes and environmental factors to their association across development. Findings suggest the need to monitor for emergence of internalizing symptoms in irritable children and their potential need for therapeutic intervention.

Psychosocial and contextual determinants of alcohol and drug use disorders in the National Latino and Asian American Study

BACKGROUND In the U.S., Latino and Asian American immigrants and ethnic minorities may be at increased risk for alcohol and drug use disorders (AUDs/DUDs). The role of psychosocial and contextual characteristics as potential factors underlying this increased risk is unresolved. METHODS Participants include 4649 adults from the National Latino and Asian American Study. Logistic regression was used to determine the relationship between acculturation, acculturative stress, neighborhood characteristics, family characteristics, and discrimination and AUDs/DUDs. Models were stratified by age of immigration and ethnicity and controlled for demographic and mental health characteristics. RESULTS Overall, 9.6% of Latino and 4.1% of Asian participants met criteria for lifetime AUDs/DUDs. Acculturation, family conflict, and discrimination were positively associated with AUDs/DUDs (odds ratios [ORs] and 95% confidence intervals [95%CIs]: 1.80[1.54-2.09], 1.24[1.12-1.36], and 1.54[1.38-1.73]), while neighborhood safety and family cohesion were protective for AUDs/DUDs (ORs[95%CIs]: 0.75[0.66-0.85] and 0.79[0.69-0.90]). Acculturative stress and neighborhood cohesion were not related to AUDs/DUDs. The relationships between family conflict and family cohesion with AUDs/DUDs were attenuated after accounting for other psychosocial and contextual factors. These relationships were generally consistent across ethnic and age of immigration subgroups. CONCLUSIONS Factors such as acculturation, discrimination, and neighborhood safety, are robustly and largely universally related to AUDs/DUDs among first and later generation Latino and Asian immigrants. Further research is required to understand how and why these factors relate to risk of substance misuse, and to identify ways to apply these factors in prevention and intervention efforts.

Validation of candidate anxiety disorder genes using a carbon dioxide challenge task.

Few replicable genetic variants have been identified in the etiology of heritable anxiety disorders such as panic disorder. Endophenotypic measures that have reduced heterogeneity may provide more powerful targets for gene identification. We assessed hypersensitivity to carbon dioxide (a reliable endophenotype of panic and anxiety) in 174 Caucasian college students, who were genotyped on 26 polymorphic markers from 11 genes previously associated with panic/anxiety. Individual trajectories of respiratory and subjective anxiety response to carbon dioxide were measured and tested for association with these genetic markers. One marker in the acid-sensing ion channel 1 (ASIC1) gene, rs1108923, had a significant association with respiratory rate. No genes had a significant association with subjective anxiety response. Our findings support previously reported associations between ASIC1 and panic/anxiety, but not other genes previously associated with anxiety disorders. The use of endophenotypic markers is a promising avenue for gene identification in anxiety and other complex disorders.

The genetics of anxiety‐related negative valence system traits

NIMHs Research Domain Criteria (RDoC) domain of negative valence systems (NVS) captures constructs of negative affect such as fear and distress traditionally subsumed under the various internalizing disorders. Through its aims to capture dimensional measures that cut across diagnostic categories and are linked to underlying neurobiological systems, a large number of phenotypic constructs have been proposed as potential research targets. Since “genes” represent a central “unit of analysis” in the RDoC matrix, it is important for studies going forward to apply what is known about the genetics of these phenotypes as well as fill in the gaps of existing knowledge. This article reviews the extant genetic epidemiological data (twin studies, heritability) and molecular genetic association findings for a broad range of putative NVS phenotypic measures. We find that scant genetic epidemiological data is available for experimentally derived measures such as attentional bias, peripheral physiology, or brain‐based measures of threat response. The molecular genetic basis of NVS phenotypes is in its infancy, since most studies have focused on a small number of candidate genes selected for putative association to anxiety disorders (ADs). Thus, more research is required to provide a firm understanding of the genetic aspects of anxiety‐related NVS constructs.

The Twin Study of Negative Valence Emotional Constructs.

The Twin Study of Negative Valence Emotional Constructs is a multi-site study designed to examine the relationship between a broad selection of potential measures designed to assess putative endophenotypes for negative valence systems (NVS) and early symptoms of internalizing disorders (IDs). In this article, we describe the sample characteristics, data collection protocols, and measures used. Pre-adolescent Caucasian twin pairs were recruited through the Mid-Atlantic Twin Registry; data collection began in February of 2013. Enrolled twins completed various dimensional self-report measures along with cognitive, emotional, and psychophysiological tasks designed to assess NVS function. Parents also completed surveys about their twins and themselves. In addition, a subset of the twins also participated in a neuroimaging protocols. Data collection is in the final stages, and preliminary analyses are underway. The findings will potentially expand our understanding of the mechanisms by which genetic and environmental factors contribute to individual differences in NVS phenotypes and provide new insights into underlying risk factors for IDs.

Personality and Gambling Involvement: A Person-Centered Approach

Individual differences in personality are likely to play an important role in explaining the propensity to gamble. One of the potential roadblocks to elucidating the relation between personality and gambling may be inadequately accounting for the diversity of gambling activities. The goal of the present study was to provide a comprehensive and nuanced portrait of the relation between personality and gambling by taking a multivariate approach to the co-use of multiple gambling activities and employing a broad inventory of potentially relevant personality dimensions. Participants were 4,669 individuals from a national Australian twin registry. Structured interviews including an extensive assessment of gambling behaviors were conducted, and personality questionnaires that included the Multidimensional Personality Questionnaire, the Sensation Seeking Scale, and the Magical Ideation Scale were completed. A latent class analysis of past-year involvement in 10 different gambling activities was performed to classify the participants into 5 groups. Unique personality configurations characterized the 3 more gambling-involved latent classes: (a) low behavioral control in the context of high negative emotionality and magical thinking typified extensive, versatile gamblers at high risk of gambling problems; (b) average behavioral control in the context of high negative emotionality and magical thinking typified those who primarily gambled on non-strategic games of chance; (c) low behavioral control in the context of high positive emotionality and low magical ideation typified those who primarily gambled on strategic games of skill. This study illustrates the value of using a multivariate person-centered approach for characterizing the personality correlates of the multifaceted phenomenon that is gambling.

Genetic meta-analysis identifies 10 novel loci and functional pathways for Alzheimer's disease risk

Late onset Alzheimer’s disease (AD) is the most common form of dementia with more than 35 million people affected worldwide, and no curative treatment available. AD is highly heritable and recent genome-wide meta-analyses have identified over 20 genomic loci associated with AD, yet only explaining a small proportion of the genetic variance indicating that undiscovered loci exist. Here, we performed the largest genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 AD cases, 383,378 controls). AD-by-proxy status is based on parental AD diagnosis, and showed strong genetic correlation with AD (rg=0.81). Genetic meta analysis identified 29 risk loci, of which 9 are novel, and implicating 215 potential causative genes. Independent replication further supports these novel loci in AD. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver and microglia). Furthermore, gene-set analyses indicate the genetic contribution of biological mechanisms involved in lipid-related processes and degradation of amyloid precursor proteins. We show strong genetic correlations with multiple health-related outcomes, and Mendelian randomisation results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying more of the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD to guide new drug development.

Molecular Genetic Influences on Normative and Problematic Alcohol Use in a Population-Based Sample of College Students

Background: Genetic factors impact alcohol use behaviors and these factors may become increasingly evident during emerging adulthood. Examination of the effects of individual variants as well as aggregate genetic variation can clarify mechanisms underlying risk. Methods: We conducted genome-wide association studies (GWAS) in an ethnically diverse sample of college students for three quantitative outcomes including typical monthly alcohol consumption, alcohol problems, and maximum number of drinks in 24 h. Heritability based on common genetic variants (h2SNP) was assessed. We also evaluated whether risk variants in aggregate were associated with alcohol use outcomes in an independent sample of young adults. Results: Two genome-wide significant markers were observed: rs11201929 in GRID1 for maximum drinks in 24 h, with supportive evidence across all ancestry groups; and rs73317305 in SAMD12 (alcohol problems), tested only in the African ancestry group. The h2SNP estimate was 0.19 (SE = 0.11) for consumption, and was non-significant for other outcomes. Genome-wide polygenic scores were significantly associated with alcohol outcomes in an independent sample. Conclusions: These results robustly identify genetic risk for alcohol use outcomes at the variant level and in aggregate. We confirm prior evidence that genetic variation in GRID1 impacts alcohol use, and identify novel loci of interest for multiple alcohol outcomes in emerging adults. These findings indicate that genetic variation influencing normative and problematic alcohol use is, to some extent, convergent across ancestry groups. Studying college populations represents a promising avenue by which to obtain large, diverse samples for gene identification.

Post-GWAS in Psychiatric Genetics: A Developmental Perspective on the “Other” Next Steps

As psychiatric genetics enters an era where gene identification is finally yielding robust, replicable genetic associations and polygenic risk scores, it is important to consider next steps and delineate how that knowledge will be applied to ultimately ameliorate suffering associated with substance use and psychiatric disorders. Much of the post‐genome‐wide association study discussion has focused on the potential of genetic information to elucidate the underlying biology and use this information for the development of more effective pharmaceutical treatments. In this review we focus on additional areas of research that should follow gene identification. By taking genetic findings into longitudinal, developmental studies, we can map the pathways by which genetic risk manifests across development, elucidating the early behavioral manifestations of risk, and studying how various environments and interventions moderate that risk across developmental stages. The delineation of risk across development will advance our understanding of mechanism, sex differences and risk and resilience processes in different racial/ethnic groups. Here, we review how the extant twin study literature can be used to guide these efforts. Together, these new lines of research will enable us to develop more informed, tailored prevention and intervention efforts.

Genetic and Environmental Contributions of Negative Valence Systems to Internalizing Pathways

The genetic and environmental contributions of negative valence systems (NVS) to internalizing pathways study (also referred to as the Adolescent and Young Adult Twin Study) was designed to examine varying constructs of the NVS as they relate to the development of internalizing disorders from a genetically informed perspective. The goal of this study was to evaluate genetic and environmental contributions to potential psychiatric endophenotypes that contribute to internalizing psychopathology by studying adolescent and young adult twins longitudinally over a 2-year period. This report details the sample characteristics, study design, and methodology of this study. The first wave of data collection (i.e., time 1) is complete; the 2-year follow-up (i.e., time 2) is currently underway. A total of 430 twin pairs (N = 860 individual twins; 166 monozygotic pairs; 57.2% female) and 422 parents or legal guardians participated at time 1. Twin participants completed self-report surveys and participated in experimental paradigms to assess processes within the NVS. Additionally, parents completed surveys to report on themselves and their twin children. Findings from this study will help clarify the genetic and environmental influences of the NVS and their association with internalizing risk. The goal of this line of research is to develop methods for early internalizing disorder risk detection.