Clinical Phenotype of Tardive Dyskinesia in Bipolar Disorder.

PURPOSE: Recognizing the negative impact that antipsychotic-induced movement disorders have on the quality of life and treatment outcomes in bipolar disorder (BD), this study aimed to assess clinical correlates and antipsychotic use patterns of tardive dyskinesia (TD+) in BD. MATERIALS AND METHODS: Participants with and without TD were included. Clinical variables were compared using t-test and χ2 test. Antipsychotic use patterns in TD+, including number of trials, mean doses, and estimated cumulative exposure, were assessed in a case-only analysis. RESULTS: The prevalence rate of TD was 5.1%. In comparison to the TD- group (n = 1074), TD+ participants (n = 58) were older, more likely to be female and have type I bipolar illness. There were 60.3% of the TD+ group that continued using antipsychotics at study entry and had a mean cumulative exposure to antipsychotics of 18.2 ± 15.6 years. Average dose, in haloperidol equivalents, was 5.9 ± 3.5 mg and 77.7% of the trials were second-generation antipsychotics. CONCLUSIONS: This study confirms previously identified TD risk factors, such as age, sex, and bipolar subtype in a large BD cohort. Limitations included a cross-sectional design and the lack of tardive illness severity assessment. As atypical antipsychotics continue to be primary mood stabilization treatment, attempting to harmonize large data sets to identify additional biomarkers of tardive risk will optimize individualized care for patients with BD.

In Vitro Effects of Ligand Bias on Primate Mu Opioid Receptor Downstream Signaling.

Interest has emerged in biased agonists at the mu opioid receptor (MOR) as a possible means for maintaining potent analgesis with reduced side effect profiles. While approaches measuring in vitro biased agonism are used in the development of these compounds, their therapeutic utility will ultimately be determined by in vivo functional effects. Nonhuman primates (NHPs) are the most translational model for evaluating the behavioral effects of candidate medications, but biased signaling of these drugs at NHP MOR receptors has been unstudied. The goal of the current work was to characterize MOR ligand bias in rhesus macaques, focusing on agonists that have previously been reported to show different patterns of biased agonism in rodents and humans. Downstream signaling pathways that responded to MOR activation were identified using a luciferase reporter array. Concentration-response curves for specific pathways (cAMP, NF-ĸB, MAPK/JNK) were generated using six agonists previously reported to differ in terms of signaling bias at rodent and human MORs. Using DAMGO as a reference ligand, relative cAMP, NF-ĸB and MAPK/JNK signaling by morphine, endomorphin-1, and TRV130 were found to be comparable between species. Further, the bias patterns of across ligands for NF-ĸB and MAPK/JNK were largely similar between species. There was a high degree of concordance between rhesus macaque and human MOR receptor signaling bias for all agonists tested, further demonstrating their utility for future translational behavioral studies.

The population genomics of rhesus macaques (Macaca mulatta) based on whole-genome sequences.

Rhesus macaques (Macaca mulatta) are the most widely used nonhuman primate in biomedical research, have the largest natural geographic distribution of any nonhuman primate, and have been the focus of much evolutionary and behavioral investigation. Consequently, rhesus macaques are one of the most thoroughly studied nonhuman primate species. However, little is known about genome-wide genetic variation in this species. A detailed understanding of extant genomic variation among rhesus macaques has implications for the use of this species as a model for studies of human health and disease, as well as for evolutionary population genomics. Whole-genome sequencing analysis of 133 rhesus macaques revealed more than 43.7 million single-nucleotide variants, including thousands predicted to alter protein sequences, transcript splicing, and transcription factor binding sites. Rhesus macaques exhibit 2.5-fold higher overall nucleotide diversity and slightly elevated putative functional variation compared with humans. This functional variation in macaques provides opportunities for analyses of coding and noncoding variation, and its cellular consequences. Despite modestly higher levels of nonsynonymous variation in the macaques, the estimated distribution of fitness effects and the ratio of nonsynonymous to synonymous variants suggest that purifying selection has had stronger effects in rhesus macaques than in humans. Demographic reconstructions indicate this species has experienced a consistently large but fluctuating population size. Overall, the results presented here provide new insights into the population genomics of nonhuman primates and expand genomic information directly relevant to primate models of human disease.

Comparative genomics of Bifidobacterium species isolated from marmosets and humans.

The genus Bifidobacterium is purported to have beneficial consequences for human health and is a major component of many gastrointestinal probiotics. Although species of Bifidobacterium are generally at low relative frequency in the adult human gastrointestinal tract, they can constitute high proportions of the gastrointestinal communities of adult marmosets. To identify genes that might be important for the maintenance of Bifidobacterium in adult marmosets, ten strains of Bifidobacterium were isolated from the feces of seven adult marmosets, and their genomes were sequenced. There were six B. reuteri strains, two B. callitrichos strains, one B. myosotis sp. nov. and one B. tissieri sp. nov. among our isolates. Phylogenetic analysis showed that three of the four species we isolated were most closely related to B. bifidum, B. breve and B. longum, which are species found in high abundance in human infants. There were 1357 genes that were shared by at least one strain of B. reuteri, B. callitrichos, B. breve, and B. longum, and 987 genes that were found in all strains of the four species. There were 106 genes found in B. reuteri and B. callitrichos but not in human bifidobacteria, and several of these genes were involved in nutrient uptake. These pathways for nutrient uptake appeared to be specific to Bifidobacterium from New World monkeys. Additionally, the distribution of Bifidobacterium in fecal samples from captive adult marmosets constituted as much as 80% of the gut microbiome, although this was variable between individuals and colonies. We suggest that nutrient transporters may be important for the maintenance of Bifidobacterium during adulthood in marmosets.

Convergent Balancing Selection on the Mu-Opioid Receptor in Primates.

The mu opioid receptor is involved in many natural processes including stress response, pleasure, and pain. Mutations in the gene also have been associated with opiate and alcohol addictions as well as with responsivity to medication targeting these disorders. Two common and mutually exclusive polymorphisms have been identified in humans, A118G (N40D), found commonly in non-African populations, and C17T (V6A), found almost exclusively in African populations. Although A118G has been studied extensively for associations and in functional assays, C17T is much less well understood. In addition to a parallel polymorphism previously identified in rhesus macaques (Macaca mulatta), C77G (P26R), resequencing in additional non-human primate species identifies further common variation: C140T (P47L) in cynomolgus macaques (Macaca fascicularis), G55C (D19H) in vervet monkeys (Chlorocebus aethiops sabeus), A111T (L37F) in marmosets (Callithrix jacchus), and C55T (P19S) in squirrel monkeys (Saimiri boliviensis peruviensis). Functional effects on downstream signaling are observed for each of these variants following treatment with the endogenous agonist ß-endorphin and the exogenous agonists morphine, DAMGO ([d-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin), and fentanyl. In addition to demonstrating the importance of functional equivalency in reference to population variation for minority health, this also shows how common evolutionary pressures have produced similar phenotypes across species, suggesting a shared response to environmental needs and perhaps elucidating the mechanism by which these organism-environment interactions are mediated physiologically and molecularly. These studies set the stage for future investigations of shared functional polymorphisms across species as a new genetic tool for translational research.

Systematic mapping of occluded genes by cell fusion reveals prevalence and stability of cis-mediated silencing in somatic cells.

Both diffusible factors acting in trans and chromatin components acting in cis are implicated in gene regulation, but the extent to which either process causally determines a cell's transcriptional identity is unclear. We recently used cell fusion to define a class of silent genes termed "cis-silenced" (or "occluded") genes, which remain silent even in the presence of trans-acting transcriptional activators. We further showed that occlusion of lineage-inappropriate genes plays a critical role in maintaining the transcriptional identities of somatic cells. Here, we present, for the first time, a comprehensive map of occluded genes in somatic cells. Specifically, we mapped occluded genes in mouse fibroblasts via fusion to a dozen different rat cell types followed by whole-transcriptome profiling. We found that occluded genes are highly prevalent and stable in somatic cells, representing a sizeable fraction of silent genes. Occluded genes are also highly enriched for important developmental regulators of alternative lineages, consistent with the role of occlusion in safeguarding cell identities. Alongside this map, we also present whole-genome maps of DNA methylation and eight other chromatin marks. These maps uncover a complex relationship between chromatin state and occlusion. Furthermore, we found that DNA methylation functions as the memory of occlusion in a subset of occluded genes, while histone deacetylation contributes to the implementation but not memory of occlusion. Our data suggest that the identities of individual cell types are defined largely by the occlusion status of their genomes. The comprehensive reference maps reported here provide the foundation for future studies aimed at understanding the role of occlusion in development and disease.

The resurgence and genetic implications of New World primates in biomedical research.

There has been a recent resurgence of interest in New World monkeys within the biomedical research community, driven by both the sequencing of the common marmoset (Callithrix jacchus) genome and a growing demand for alternatives to Old World primates. New World monkeys offer attractive advantages over Old World species, including cheaper and simpler husbandry, while still maintaining a greater evolutionary proximity to humans compared with other animal models. Although numerous commonalities across primate species exist, there are also important genetic and reproductive differences that can and should play a critical role in selecting appropriate animal models. Common marmosets in particular have significantly reduced diversity at the major histocompatibility complex (MHC) loci and are born as hematopoietic chimeras. New World primates can make ideal translational models for research, but scientists must necessarily incorporate complete understandings of their genetic and phenotypic differences from humans and other model organisms.

Genetic substructure in cynomolgus macaques (Macaca fascicularis) on the island of Mauritius.

BACKGROUND: Nonhuman primates are commonly used in biomedical research as animal models of human disease and behavior. Compared to common rodent models, nonhuman primates are genetically, physiologically, behaviorally and neurologically more similar to humans owing to more recent shared ancestry and therefore provide the advantage of greater translational validity in preclinical studies. The cynomolgus macaque (Macaca fascicularis) is one of the most commonly used nonhuman primates in academic and industry settings, yet population genetic research has revealed significant substructure throughout the species distribution that may confound studies. Cynomolgus monkeys introduced to Mauritius specifically have previously been thought to maintain the least genetic heterogeneity of all cynomolgus monkeys, although recent work, including work from our lab, suggests macaques from Mauritius too may harbor cryptic substructure. RESULTS: To evaluate putative substructure in Mauritian cynomolgus macaques, we designed a panel of 96 single nucleotide polymorphisms based on preliminary findings from previous work to screen 246 of cynomolgus monkeys from two primary suppliers. Results from this study support substructure in Mauritian macaques and suggest a minimum of two populations and maybe three on Mauritius, with moderate admixture. CONCLUSION: These findings inform the natural history of these monkeys suggesting either a previously unrecognized physical or ecological barrier to gene flow on Mauritius and/or the breakdown of historic substructure resulting from the history of macaque introduction to the island. These findings are relevant to ongoing research using these models in part because of increased appreciation of segregating common variation with functional effects and may be used to better inform animal selection in preclinical research.

Development and validation of a SNP-based assay for inferring the genetic ancestry of rhesus macaques (Macaca mulatta).

Rhesus macaques (Macaca mulatta) are an important primate model species in several areas of biomedical research. The wide geographic distribution of this species has led to significant genetic differentiation among local and regional populations. These regional differences can be important factors in the selection of the most appropriate subjects for particular research studies, as animals from different populations can respond differently to the same experimental treatment. Consequently, it is valuable to confirm the ancestry of individual rhesus monkeys from geographically distinct populations. Using DNA samples obtained from rhesus macaques from six National Primate Research Centers, we tested a set of 384 potential ancestry informative single nucleotide polymorphisms (SNPs) and identified a final panel of 91 SNPs that can reliably distinguish Indian-origin from Chinese-origin rhesus monkeys. This genetic test can be used to determine the ancestral origin of animals and to detect individuals that are hybrids between these two regional populations. To demonstrate use of the SNP panel, we investigated the ancestry of 480 animals from the Yerkes NPRC (YNPRC) for which the colony records were insufficient to clearly establish ancestry. Three of the YNPRC animals tested were determined to be hybrids. This SNP ancestry tool will be useful to researchers, colony managers, and others who wish to evaluate the ancestral origin of individual rhesus macaques, and therefore will facilitate more effective and efficient use of these animals in biomedical research.

Differentially Altered Metabolic Pathways in the Amygdala of Subjects with Schizophrenia, Bipolar Disorder and Major Depressive Disorder.

Background and hypothesis: A growing number of studies implicate a key role for metabolic processes in psychiatric disorders. Recent studies suggest that ketogenic diet may be therapeutically effective for subgroups of people with schizophrenia (SCZ), bipolar disorder (BPD) and possibly major depressive disorder (MDD). Despite this promise, there is currently limited information regarding brain energy metabolism pathways across these disorders, limiting our understanding of how brain metabolic pathways are altered and who may benefit from ketogenic diets. We conducted gene expression profiling on the amygdala, a key region involved in in the regulation of mood and appetitive behaviors, to test the hypothesis that amygdala metabolic pathways are differentially altered between these disorders. Study Design: We used a cohort of subjects diagnosed with SCZ, BPD or MDD, and non-psychiatrically ill control subjects (n=15/group), together with our bioinformatic 3-pod analysis consisting of full transcriptome pathway analysis, targeted pathway analysis, leading-edge gene analysis and iLINCS perturbagen analysis. Study Results: We identified differential expression of metabolic pathways in each disorder. Subjects with SCZ displayed downregulation of mitochondrial respiration and nucleotide metabolism pathways. In comparison, we observed upregulation of mitochondrial respiration pathways in subjects with MDD, while subjects with BPD displayed enrichment of pathways involved in carbohydrate metabolism. Several pathways associated with brain metabolism including immune system processes and calcium ion transport were also differentially altered between diagnosis groups. Conclusion: Our findings suggest metabolic pathways are differentially altered in the amygdala in these disorders, which may impact approaches for therapeutic strategies.

Comparison of the reinforcing, antinociceptive, and respiratory depressant effects of prototypical and G-protein biased mu-opioid receptor agonists in male and female Sprague-Dawley rats.

RATIONALE: G-protein biased mu-opioid receptor (MOR) agonists have been reported to exhibit superior therapeutic windows compared to prototypical MOR agonists when relating antinociception to respiratory depression. However, there is relatively little research on the abuse potential of G-protein biased MOR agonists in relation to other behavioral endpoints. OBJECTIVES: The aim of the present study was to quantitatively compare the reinforcing, antinociceptive, and respiratory-depressant effects of the prototypical MOR agonists, fentanyl and oxycodone, to the G-protein biased MOR agonists, SR14968 and SR17018, in male and female rats. METHODS: In the self-administration study, four separate groups of Sprague-Dawley (SD) rats self-administered intravenous (i.v.) fentanyl, oxycodone, SR14968, and SR17018 under a progressive-ratio schedule of reinforcement. Using a within-subjects design, separate cohorts of SD rats were tested with i.v. fentanyl, oxycodone, SR14968, and SR17018 using a hot-plate assay, assays of neuropathic and inflammatory antinociception, and whole-body plethysmography. RESULTS: All MOR agonists functioned as reinforcers, but SR14968 and SR17018 were less efficacious relative to oxycodone and fentanyl. Moreover, all MOR agonists produced dose-dependent and fully efficacious antinociception across all nociception modalities. Oxycodone and fentanyl, but not SR14968 or SR17018, produced respiratory depression in a dose-dependent manner. CONCLUSION: The present results indicate that the G-protein biased MOR agonists tested herein produce MOR-typical antinociception, exhibit reduced but apparent abuse potential, and do not produce respiratory effects at doses that are above the antinociceptive range. Atypical MOR agonists within the SR series should be further studied as foundational molecules for the development of safter analgesics.

Omics Approaches to Investigate the Pathogenesis of Suicide.

Suicide is the second leading cause of death in U.S. adolescents and young adults and is generally associated with a psychiatric disorder. Suicidal behavior has a complex etiology and pathogenesis. Moderate heritability suggests genetic causes. Associations between childhood and recent life adversity indicate contributions from epigenetic factors. Genomic contributions to suicide pathogenesis remain largely unknown. This article is based on a workshop held to design strategies to identify molecular drivers of suicide neurobiology that would be putative new treatment targets. The panel determined that while bulk tissue studies provide comprehensive information, single-nucleus approaches that identify cell type-specific changes are needed. While single-nuclei techniques lack information on cytoplasm, processes, spines, and synapses, spatial multiomic technologies on intact tissue detect cell alterations specific to brain tissue layers and subregions. Because suicide has genetic and environmental drivers, multiomic approaches that combine cell type-specific epigenome, transcriptome, and proteome provide a more complete picture of pathogenesis. To determine the direction of effect of suicide risk gene variants on RNA and protein expression and how these interact with epigenetic marks, single-nuclei and spatial multiomics quantitative trait loci maps should be integrated with whole-genome sequencing and genome-wide association databases. The workshop concluded with a recommendation for the formation of an international suicide biology consortium that will bring together brain banks and investigators with expertise in cutting-edge omics technologies to delineate the biology of suicide and identify novel potential treatment targets to be tested in cellular and animal models for drug and biomarker discovery to guide suicide prevention.

Large-scale polymorphism discovery in macaque G-protein coupled receptors.

BACKGROUND: G-protein coupled receptors (GPCRs) play an inordinately large role in human health. Variation in the genes that encode these receptors is associated with numerous disorders across the entire spectrum of disease. GPCRs also represent the single largest class of drug targets and associated pharmacogenetic effects are modulated, in part, by polymorphisms. Recently, non-human primate models have been developed focusing on naturally-occurring, functionally-parallel polymorphisms in candidate genes. This work aims to extend those studies broadly across the roughly 377 non-olfactory GPCRs. Initial efforts include resequencing 44 Indian-origin rhesus macaques (Macaca mulatta), 20 Chinese-origin rhesus macaques, and 32 cynomolgus macaques (M. fascicularis). RESULTS: Using the Agilent target enrichment system, capture baits were designed for GPCRs off the human and rhesus exonic sequence. Using next generation sequencing technologies, nearly 25,000 SNPs were identified in coding sequences including over 14,000 non-synonymous and more than 9,500 synonymous protein-coding SNPs. As expected, regions showing the least evolutionary constraint show greater rates of polymorphism and greater numbers of higher frequency polymorphisms. While the vast majority of these SNPs are singletons, roughly 1,750 non-synonymous and 2,900 synonymous SNPs were found in multiple individuals. CONCLUSIONS: In all three populations, polymorphism and divergence is highly concentrated in N-terminal and C-terminal domains and the third intracellular loop region of GPCRs, regions critical to ligand-binding and signaling. SNP frequencies in macaques follow a similar pattern of divergence from humans and new polymorphisms in primates have been identified that may parallel those seen in humans, helping to establish better non-human primate models of disease.

Nonhuman primate genetic models for the study of rare diseases.

Pre-clinical research and development relies heavily upon translationally valid models of disease. A major difficulty in understanding the biology of, and developing treatments for, rare disease is the lack of animal models. It is important that these models not only recapitulate the presentation of the disease in humans, but also that they share functionally equivalent underlying genetic causes. Nonhuman primates share physiological, anatomical, and behavioral similarities with humans resulting from close evolutionary relationships and high genetic homology. As the post-genomic era develops and next generation sequencing allows for the resequencing and screening of large populations of research animals, naturally occurring genetic variation in nonhuman primates with clinically relevant phenotypes is regularly emerging. Here we review nonhuman primate models of multiple rare genetic diseases with a focus on the similarities and differences in manifestation and etiologies across species. We discuss how these models are being developed and how they can offer new tools and opportunities for researchers interested in exploring novel therapeutics for these and other genetic diseases. Modeling human genetic diseases in translationally relevant nonhuman primates presents new prospects for development of therapeutics and a better understanding of rare diseases. The post-genomic era offers the opportunity for the discovery and further development of more models like those discussed here.

Comparison of Demographic and Clinical Features of Bipolar Disorder in Persons of African and European Ancestry.

AIM: This study quantified and compared demographic and clinical features of bipolar disorder (BD) in persons of African ancestry (AA) and European ancestry (EUR). METHODS: Participants enrolled in the Mayo Clinic Bipolar Biobank from 2009 to 2015. The structured clinical interview for DSM-IV was used to confirm the diagnosis of BD, and a questionnaire was developed to collect data on the clinical course of illness. Descriptive statistics and bivariate analyses were completed to compare AA versus EUR participants. Subsequently, clinical outcomes were compared between AA and EUR participants using linear regression for continuous outcomes or logistic regression for binary outcomes while controlling for differences in age, sex, and recruitment site. RESULTS: Of 1865 participants enrolled in the bipolar biobank, 65 (3.5%) self-identified as AA. The clinical phenotype for AA participants, in comparison to EUR participants, was more likely to include a history of PTSD (39.7% vs. 26.2%), cocaine use disorder (24.2% vs. 11.9%), and tardive dyskinesia (7.1% vs. 3%). CONCLUSION: The low rate of AA enrollment is consistent with other genetic studies. While clinical features of bipolar disorder are largely similar, this study identified differences in rates of trauma, substance use, and tardive dyskinesia that may represent health disparities in bipolar patients of African ancestry. Future bipolar biomarker studies with larger sample sizes focused on underrepresented populations will provide greater ancestry diversity in genomic medicine with greater applicability to diverse patient populations, serving to inform health care policies to address disparities in bipolar disorder.

Quantitative molecular assessment of chimerism across tissues in marmosets and tamarins.

BACKGROUND: Marmosets are playing an increasingly large and important role in biomedical research. They share genetic, anatomical, and physiological similarities with humans and other primate model species, but their smaller sizes, reproductive efficiency, and amenability to genetic manipulation offer an added practicality. While their unique biology can be exploited to provide insights into disease and function, it is also important that researchers are aware of the differences that exist between marmosets and other species. The New World monkey family Callitrichidae, containing both marmoset and tamarin species, typically produces dizygotic twins that show chimerism in the blood and other cells from the hematopoietic lineage. Recently, a study extended these findings to identify chimerism in many tissues, including somatic tissues from other lineages and germ cells. This has raised the intriguing possibility that chimerism may play an increasingly pervasive role in marmoset biology, ranging from natural behavioral implications to increased variability and complexity in biomedical studies. RESULTS: Using a quantitative PCR based methodology, Y-chromosomes can be reliably detected in the females with male fraternal twins allowing for a relative quantification of chimerism levels between individuals and tissues. With this approach in common marmosets (Callithrix jacchus) and cotton-top tamarins (Saguinus oedipus), chimerism was detected across a broad array of tissues. Chimerism levels were significantly higher in tissues primarily derived from the hematopoietic lineage, while they were lower, though still detectable, in tissues with other origins. Interestingly, animals with a characteristic marmoset wasting disease show higher levels of chimerism in those tissues affected. Fibroblast cell lines from chimeric individuals, however, are not found to be chimeric themselves. CONCLUSION: Taken together, the levels of chimerism in tissues of different origins coupled with other lines of evidence suggest that indeed only hematopoietic cell lineages are chimeric in callitrichids. The chimerism detected in other tissues is likely the result of blood or lymphocytic infiltration. Using molecular methods to detect chimerism in a tissue sample seems to have allowed a substantial increase in the ability to detect these minor cell populations.

Growth-associated protein-43 and ephrin B3 induction in the brain of adult SIV-infected rhesus macaques.

Understanding the mechanisms of neuronal regeneration and repair in the adult central nervous system is a vital area of research. Using a rhesus lentiviral encephalitis model, we sought to determine whether recovery of neuronal metabolism after injury coincides with the induction of two important markers of synaptodendritic repair: growth-associated protein-43 (GAP-43) and ephrin B3. We examined whether the improvement of neuronal metabolism with combined anti-retroviral therapy (cART) after simian immunodeficiency virus (SIV) infection in rhesus macaques involved induction of GAP-43, also known as neuromodulin, and ephrin B3, both implicated in axonal pathfinding during neurodevelopment and regulation of synapse formation, neuronal plasticity, and repair in adult brain. We utilized magnetic resonance spectroscopy to demonstrate improved neuronal metabolism in vivo in adult SIV-infected cART animals compared to untreated and uninfected controls. We then assessed levels of GAP-43, ephrin B3, and synaptophysin, a pre-synaptic marker, in three brain regions important for cognitive function, cortex, hippocampus, and putamen, by quantitative real-time RT-PCR and immunohistochemistry. Here we demonstrate that (1) GAP-43 mRNA and protein are induced with SIV infection, (2) GAP-43 protein is higher in the hippocampus outer molecular layer in SIV-infected animals that received cART compared to those that did not, and (3) activated microglia and infiltrating SIV-infected macrophages express abundant ephrin B3, an important axonal guidance molecule. We propose a model whereby SIV infection triggers events that lead to induction of GAP-43 and ephrin B3, and that short-term cART results in increased magnitude of repair mechanisms especially in the hippocampus, a region known for high levels of adult plasticity.

Comparative genetic approaches to the evolution of human brain and behavior.

With advances in genomic technologies, the amount of genetic data available to scientists today is vast. Genomes are now available or planned for 14 different primate species and complete resequencing of numerous human individuals from numerous populations is underway. Moreover, high-throughput deep sequencing is quickly making whole genome efforts within the reach of single laboratories allowing for unprecedented studies. Comparative genetic approaches to the identification of the underlying basis of human brain, behavior, and cognitive ability are moving to the forefront. Two approaches predominate: inter-species divergence comparisons and intra-species polymorphism studies. These methodological differences are useful for different time scales of evolution and necessarily focus on different evolutionary events in the history of primate and hominin evolution. Inter-species divergence is more useful in studying large scale primate, or hominoid, evolution whereas intra-species polymorphism can be more illuminating of recent hominin evolution. These differences in methodological utility also extend to studies of differing genetic substrates; current divergence studies focus primarily on protein evolution whereas polymorphism studies are substrate ambivalent. Some of the issues inherent in these studies can be ameliorated by current sequencing capabilities whereas others remain intractable. New avenues are also being opened that allow for the incorporation of novel substrates and approaches. In the post-genomic era, the study of human evolution, specifically as it relates to the brain, is becoming more complete focusing increasingly on the totality of the system and better conceptualizing the entirety of the genetic changes that have lead to the human phenotype today.

Motivating and Discouraging Factors for Bipolar Patient Participation in Genomic Research.

AIMS: The goal of this project was to better understand the motivating and discouraging factors toward genetic research and biobank programs in patients with bipolar disorder, particularly across gender and racial identities. METHODS: A survey (n = 63) of adults diagnosed with bipolar disorder was conducted at the general psychiatric inpatient unit and outpatient clinic at the University of Mississippi Medical Center. Participants were asked to rate on a Likert scale their attitudes toward medical research generally, mental health research specifically, and willingness to participate in a bipolar DNA biobank. Last, they were asked to endorse motivating factors or concerns for their attitude toward participation. RESULTS: Neither attitudes toward research nor willingness to participate in a bipolar biobank differed across gender, age, or education level, but Black/African American participants were statistically significantly less likely to endorse a willingness to participate in a biobank compared to White participants. As observed in previous work, Black/African American participants were significantly more likely to endorse concerns regarding violations of trust, privacy, or autonomy. However, while there were no significant differences in discouraging factors among individuals who indicated an opposition to participating in a biobank compared to those who indicated support, there was a significant decrease in support of motivating factors, including increasing knowledge, personal benefit, and duty to community, for those not interested in participating. CONCLUSIONS: Black/African American participants with bipolar disorder were more likely to express concerns about DNA and biobank research. But while race was a contributing factor to support or opposition to biobanking for bipolar disorder research, more salient was insufficient positive motivation. These results highlight the need to emphasize contemporary safeguards on DNA research and biobanking as an ethical duty and to identify the need for community-based educational interventions to promote a greater understanding of the positive benefits to motivate increased research participation.

The roles of borderline personality disorder symptoms and dispositional capability for suicide in suicidal ideation and suicide attempts: Examination of the COMT Val158Met polymorphism.

There is a need to identify the subset of individuals with borderline personality disorder (BPD) symptoms at greatest risk for transitioning from suicidal ideation to a suicide attempt. Contemporary models of suicide risk propose that the capability for suicide is necessary for moving from suicidal ideation to a suicide attempt. Few studies have examined dispositional capability factors for suicide, especially among individuals with BPD symptoms. One candidate may be the catechol-o-methyltransferase (COMT) Val158Met polymorphism given its influence on pain sensitivity and fear. This study examined the interactive relation of BPD symptoms and the COMT Val158Met polymorphism to suicidal ideation and suicide attempts. Fifty-nine treatment-seeking patients were recruited. Participants were administered a series of clinical interviews to evaluate BPD symptoms and suicidal thoughts and behaviors. Saliva samples were collected for genotyping. The relation between BPD symptoms and suicidal ideation was not influenced by the Val158Met polymorphism. However, among Val/Val carriers, the probability of a lifetime suicide attempt increased as BPD symptom severity increased. Findings provide preliminary support for the Val/Val variant as a dispositional factor that may increase risk for suicide attempts in BPD; however, results must be interpreted with caution until replication of findings occurs in larger samples.