Maria Hipolito

Genome-wide association study of bipolar disorder in European American and African American individuals

To identify bipolar disorder (BD) genetic susceptibility factors, we conducted two genome-wide association (GWA) studies: one involving a sample of individuals of European ancestry (EA; n=1001 cases; n=1033 controls), and one involving a sample of individuals of African ancestry (AA; n=345 cases; n=670 controls). For the EA sample, single-nucleotide polymorphisms (SNPs) with the strongest statistical evidence for association included rs5907577 in an intergenic region at Xq27.1 (P=1.6 × 10−6) and rs10193871 in NAP5 at 2q21.2 (P=9.8 × 10−6). For the AA sample, SNPs with the strongest statistical evidence for association included rs2111504 in DPY19L3 at 19q13.11 (P=1.5 × 10−6) and rs2769605 in NTRK2 at 9q21.33 (P=4.5 × 10−5). We also investigated whether we could provide support for three regions previously associated with BD, and we showed that the ANK3 region replicates in our sample, along with some support for C15Orf53; other evidence implicates BD candidate genes such as SLITRK2. We also tested the hypothesis that BD susceptibility variants exhibit genetic background-dependent effects. SNPs with the strongest statistical evidence for genetic background effects included rs11208285 in ROR1 at 1p31.3 (P=1.4 × 10−6), rs4657247 in RGS5 at 1q23.3 (P=4.1 × 10−6), and rs7078071 in BTBD16 at 10q26.13 (P=4.5 × 10−6). This study is the first to conduct GWA of BD in individuals of AA and suggests that genetic variations that contribute to BD may vary as a function of ancestry.

Singleton deletions throughout the genome increase risk of bipolar disorder.

An overall burden of rare structural genomic variants has not been reported in bipolar disorder (BD), although there have been reports of cases with microduplication and microdeletion. Here, we present a genome-wide copy number variant (CNV) survey of 1001 cases and 1034 controls using the Affymetrix single nucleotide polymorphism (SNP) 6.0 SNP and CNV platform. Singleton deletions (deletions that appear only once in the dataset) more than 100 kb in length are present in 16.2% of BD cases in contrast to 12.3% of controls (permutation P=0.007). This effect was more pronounced for age at onset of mania ⩽18 years old. Our results strongly suggest that BD can result from the effects of multiple rare structural variants.

Enrichment of cis-regulatory gene expression SNPs and methylation quantitative trait loci among bipolar disorder susceptibility variants

We conducted a systematic study of top susceptibility variants from a genome-wide association (GWA) study of bipolar disorder to gain insight into the functional consequences of genetic variation influencing disease risk. We report here the results of experiments to explore the effects of these susceptibility variants on DNA methylation and mRNA expression in human cerebellum samples. Among the top susceptibility variants, we identified an enrichment of cis regulatory loci on mRNA expression (eQTLs), and a significant excess of quantitative trait loci for DNA CpG methylation, hereafter referred to as methylation quantitative trait loci (mQTLs). Bipolar disorder susceptibility variants that cis regulate both cerebellar expression and methylation of the same gene are a very small proportion of bipolar disorder susceptibility variants. This finding suggests that mQTLs and eQTLs provide orthogonal ways of functionally annotating genetic variation within the context of studies of pathophysiology in brain. No lymphocyte mQTL enrichment was found, suggesting that mQTL enrichment was specific to the cerebellum, in contrast to eQTLs. Separately, we found that using mQTL information to restrict the number of single-nucleotide polymorphisms studied enhances our ability to detect a significant association. With this restriction a priori informed by the observed functional enrichment, we identified a significant association (rs12618769, Pbonferroni<0.05) from two other GWA studies (TGen+GAIN; 2191 cases and 1434 controls) of bipolar disorder, which we replicated in an independent GWA study (WTCCC). Collectively, our findings highlight the importance of integrating functional annotation of genetic variants for gene expression and DNA methylation to advance the biological understanding of bipolar disorder.

Sleep disturbances in the aftermath of trauma and posttraumatic stress disorder.

Sleep disturbances, including nightmares and insomnia, are prominent following trauma and with posttraumatic stress disorder (PTSD) and likely contribute to the pathogenesis of the disorder. Findings from laboratory studies of PTSD have been inconsistent in terms of documenting objective impaired sleep maintenance but have been somewhat more consistent in indicating alterations of rapid eye movement (REM) sleep. Studies of the early aftermath of trauma can reduce the complexity associated with chronicity and comorbidity, and may have implications for early diagnosis and prevention. Multiple studies indicate that dream content is affected by recent threatening experiences. The development of PTSD is associated with a more replicative type of nightmare content. Sleep is reported to be generally disrupted following trauma especially among those developing PTSD. The limited number of studies that provide objective recorded indices during the early aftermath of trauma also provide a mixed picture regarding overall sleep maintenance. Recent data suggest that a more specific disruption of REM sleep may be associated with the development of PTSD and that this disruption is associated with an increased signal of sympathetic nervous system activation during REM sleep. Disrupted REM sleep and increased sympathetic/noradrenergic activity may have implications for understanding recent promising interventions for PTSD sleep disturbance that can be applied to early intervention.

Genome-wide linkage and follow-up association study of postpartum mood symptoms

OBJECTIVE Family studies have suggested that postpartum mood symptoms might have a partly genetic etiology. The authors used a genome-wide linkage analysis to search for chromosomal regions that harbor genetic variants conferring susceptibility for such symptoms. The authors then fine-mapped their best linkage regions, assessing single nucleotide polymorphisms (SNPs) for genetic association with postpartum symptoms. METHOD Subjects were ascertained from two studies: the NIMH Genetics Initiative Bipolar Disorder project and the Genetics of Recurrent Early-Onset Depression. Subjects included women with a history of pregnancy, any mood disorder, and information about postpartum symptoms. In the linkage study, 1,210 women met criteria (23% with postpartum symptoms), and 417 microsatellite markers were analyzed in multipoint allele sharing analyses. For the association study, 759 women met criteria (25% with postpartum symptoms), and 16,916 SNPs in the regions of the best linkage peaks were assessed for association with postpartum symptoms. RESULTS The maximum linkage peak for postpartum symptoms occurred on chromosome 1q21.3-q32.1, with a chromosome-wide significant likelihood ratio Z score (Z(LR)) of 2.93 (permutation p=0.02). This was a significant increase over the baseline Z(LR) of 0.32 observed at this locus among all women with a mood disorder (permutation p=0.004). Suggestive linkage was also found on 9p24.3-p22.3 (Z(LR)=2.91). In the fine-mapping study, the strongest implicated gene was HMCN1 (nominal p=0.00017), containing four estrogen receptor binding sites, although this was not region-wide significant. CONCLUSIONS This is the first study to examine the genetic etiology of postpartum mood symptoms using genome-wide data. The results suggest that genetic variations on chromosomes 1q21.3-q32.1 and 9p24.3-p22.3 may increase susceptibility to postpartum mood symptoms.

Genome-wide association of bipolar disorder suggests an enrichment of replicable associations in regions near genes.

Although a highly heritable and disabling disease, bipolar disorders (BD) genetic variants have been challenging to identify. We present new genotype data for 1,190 cases and 401 controls and perform a genome-wide association study including additional samples for a total of 2,191 cases and 1,434 controls. We do not detect genome-wide significant associations for individual loci; however, across all SNPs, we show an association between the power to detect effects calculated from a previous genome-wide association study and evidence for replication (P = 1.5×10−7). To demonstrate that this result is not likely to be a false positive, we analyze replication rates in a large meta-analysis of height and show that, in a large enough study, associations replicate as a function of power, approaching a linear relationship. Within BD, SNPs near exons exhibit a greater probability of replication, supporting an enrichment of reproducible associations near functional regions of genes. These results indicate that there is likely common genetic variation associated with BD near exons (±10 kb) that could be identified in larger studies and, further, provide a framework for assessing the potential for replication when combining results from multiple studies.

Posttraumatic Stress Disorder and Nocturnal Blood Pressure Dipping in Young Adult African Americans

Objective: To evaluate the relationship between posttraumatic stress disorder (PTSD) and nocturnal blood pressure (BP) dipping in young adult African Americans (AAs). PTSD is associated with physical illnesses including cardiovascular conditions. Sleep disturbances related to heightened arousal likely contribute to physical health risk; however, this possibility has not been studied. The studies that have found a relationship between PTSD and hypertension (HTN) have substantial representation of AAs. AAs have elevated rates of HTN and are more likely to exhibit an absence of the normal “dip” of BP at night. Nocturnal BP “nondipping” is an established risk factor for HTN and its cardiovascular complications. Nocturnal BP nondipping and sleep disturbances of PTSD have both been linked to sympathetic nervous system function. Methods: Thirty healthy young adult AAs (60% female; mean age = 20.0 years; 17 with lifetime full or subthreshold PTSD, 4 with current symptoms) received 24-hour BP and actigraphy monitoring, filled out sleep diaries, and had structured clinical assessment of PTSD. Results: There were significant associations of lifetime full and subthreshold PTSD and BP nondipping, and the degree of nocturnal dipping correlated with lifetime and current PTSD severity. Conclusion: Elevated nocturnal BP may be a link between PTSD and cardiovascular morbidity in AAs that can be targeted in prevention. PTSD = posttraumatic stress disorder; AA = African American; HTN = hypertension; BP = blood pressure; SNS = sympathetic nervous system; MAP = mean arterial pressure; CAPS = Clinician Administered PTSD Scale.

Meanings of Recovery From the Perspective of People With Dual Diagnosis

Objective: “Creating Communities” is a research project that examines processes of recovery within small housing communities of people living with co-occurring mental illness and substance use disorders. The authors label these configurations recovery communities. All recovery communities are owned and managed by one community mental health agency. This article reports preliminary findings on perspectives of the meaning of recovery for people living in these communities. Methods: Focus groups have been conducted at 4-month intervals with residents at recovery communities since 2005. The present analysis draws on data collected in 2009 and 2010, when the authors began systematically inquiring into meanings of recovery. Focus group transcripts were reviewed to identify prominent themes. First-person perspectives were used to provide a description of the meanings of recovery among residents in recovery communities. Results: Recovery is a multifaceted concept for individuals living with co-occurring disorders. Our preliminary analysis yielded three key dimensions of the meaning of recovery: (a) acknowledgment, (b) present orientation, and (c) transformation and growth. Conclusions: Our preliminary analysis systematically articulates core dimensions of the concept of recovery from the perspectives of consumers with dual diagnosis. It is our hope that this article will contribute to the development of an integrated vision of recovery-oriented services.

Genome-Wide Association Study of Irritable vs. Elated Mania Suggests Genetic Differences between Clinical Subtypes of Bipolar Disorder

The use of clinical features to define subtypes of a disorder may aid in gene identification for complex diseases. In particular, clinical subtypes of mania may distinguish phenotypic subgroups of bipolar subjects that may also differ genetically. To assess this possibility, we performed a genome-wide association study using genotype data from the Bipolar Genome Study (BiGS) and subjects that were categorized as having either irritable or elated mania during their most severe episode. A bipolar case-only analysis in the GAIN bipolar sample identified several genomic regions that differed between irritable and elated subjects, the most significant of which was for 33 SNPs on chromosome 13q31 (peak p = 2×10−7). This broad peak is in a relative gene desert over an unknown EST and between the SLITRK1 and SLITRK6 genes. Evidence for association to this region came predominantly from subjects in the sample that were originally collected as part of a family-based bipolar linkage study, rather than those collected as bipolar singletons. We then genotyped an additional sample of bipolar singleton cases and controls, and the analysis of irritable vs. elated mania in this new sample did not replicate our previous findings. However, this lack of replication is likely due to the presence of significant differences in terms of clinical co-morbity that were identified between these singleton bipolar cases and those that were selected from families segregating the disorder. Despite these clinical differences, analysis of the combined sample provided continued support for 13q31 and other regions from our initial analysis. Though genome-wide significance was not achieved, our results suggest that irritable mania results from a distinct set of genes, including a region on chromosome 13q31.

Ethnic disparities in the perception of ethical risks from psychiatric genetic studies

To examine if ethnic differences in concerns about unfavorable consequences from psychiatric genetic studies, existing between non‐Hispanic Black and White populations, persist among participants in an actual genetic study of bipolar disorder. Historically, minority subjects have been less willing to participate in such studies. Participants in the US Bipolar Genome Study (BIGS) were assessed on six items of concerns in the Questionnaire on Genetic Risk (QGR). Each item had five response categories, ranging from “not at all” concerned to “very concerned.” Responses from Black (N = 188) and White participants (N = 1,065) formed the base for this analysis. Concerns about unfavorable consequences of conducting psychiatric genetic studies were prevalent in the whole sample. Concern for medical insurance was most prevalent (63.4%), followed by job concern (58.8%) and stigma (57.4%). Racial discrimination was less prevalent (28.1%). Blacks endorsed significantly stronger concerns for all consequences except the medical insurance item (P < 0.008). The most significant ethnic disparity in concerns was for racial discrimination (P < 0.0001). Associations between levels of concern and ethnicity remained significant after adjustments for other factors in multivariate models. Ethnic differences (Blacks vs. Whites) in perceived concerns about unfavorable consequences from participation persist among participants in an actual psychiatric genetic study. This suggests that other factors may play a more critical role in the decision not to participate. Future studies should investigate more comprehensive sources of barriers to consenting for ongoing psychiatric genetic studies in representative samples, incorporating assessments from non‐participants as well as participants.