James L Kennedy

BackgroundBrain-derived neurotrophic factor (BDNF) has been widely studied as a vulnerability factor for mental health disorders and is involved in learning and memory. We examined the association among the BDNF Val66Met genetic polymorphism (rs6265/G196A), risk for borderline personality disorder (BPD), and common co-morbidities of BPD (post-traumatic stress disorder (PTSD) and eating disorders (ED)). Furthermore, in this treatment study we were uniquely able to examine Val66Met in response to psychotherapy.MethodsData from 246 participants with BPD (82.1 % female, all white ancestry by self-report) were drawn from two randomized controlled trials. The association among BDNF Val66Met and comorbid ED and PTSD, as well as psychotherapy response was explored using chi-square analyses. The distribution of BDNF Val66Met in our BPD sample was also compared to the general population …

Post-traumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 new). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (for example, GRIA1, GRM8 and CACNA1E), developmental, axon guidance and transcription factors (for example, FOXP2, EFNA5 and DCC), synaptic structure and function genes (for example, PCLO, NCAM1 and PDE4B) and endocrine or immune …

Objectives The pathology of Tardive Dyskinesia (TD) has yet to be fully understood, but there have been proposed hypotheses for the cause of this condition. Our team previously reported a possible association of TD with the Complement Component C4 gene in the HLA region. In this study, we explored the HLA region further by examining two previously identified schizophrenia‐associated HLA‐region single‐nucleotide polymorphisms (SNPs), namely rs13194504 and rs210133. Methods The SNPs rs13194504 and rs210133 were tested for association with the occurrence and severity of TD in a sample of 172 schizophrenia patients who were recruited for four studies from three different clinical sites in Canada and USA. Results The rs13194504 AA genotype was associated with decreased severity for TD as measured by Abnormal Involuntary Movement Scale (AIMS) scores (p = 0.047) but not for TD …

Schizophrenia is a severe mental illness and a major risk factor for suicide, with approximately 50% of schizophrenia patients attempting and 10% dying from suicide. Although genetic components play a significant role in schizophrenia risk, the underlying genetic risk factors for suicide are poorly understood. The complement component C4 gene, an immune gene involved in the innate immune system and located in the major histocompatibility complex (MHC) region, has been identified to be strongly associated with schizophrenia risk. In addition, recent findings have also suggested that the MHC region has been associated with suicide risk across disorders, making C4 a potential candidate of interest for studying suicidality in schizophrenia patients. Despite growing interest in investigating the association between the C4 gene and schizophrenia, to our knowledge, no work has been done to examine the potential …

BackgroundReduced vagally-mediated heart rate variability (HRV) has been associated with anxiety disorders (AD). The aim of this study was to use a wearable device and remote study design to re-evaluate the association of HRV with ADs, anxiety-related traits, and confounders.Methods240 individuals (AD = 120, healthy controls = 120) completed an at-home assessment of their short-term resting vagally-mediated HRV using a wristband, monitored over videoconference. Following quality control, analyses were performed investigating differences in HRV between individuals with AD (n = 119) and healthy controls (n = 116), associations of HRV with anxiety-related traits and confounders, and antidepressants effects on HRV in patients, including analyses stratified by ancestry (i.e., European, East Asian, African).ResultsAmong the confounders investigated, only age had a significant association with HRV …

Obsessive-compulsive disorder (OCD) affects ~1% of the population and exhibits a high SNP-heritability, yet previous genome-wide association studies (GWAS) have provided limited information on the genetic etiology and underlying biological mechanisms of the disorder. We conducted a GWAS meta-analysis combining 53,660 OCD cases and 2,044,417 controls from 28 European-ancestry cohorts revealing 30 independent genome-wide significant SNPs and a SNP-based heritability of 6.7%. Separate GWAS for clinical, biobank, comorbid, and self-report sub-groups found no evidence of sample ascertainment impacting our results. Functional and positional QTL gene-based approaches identified 249 significant candidate risk genes for OCD, of which 25 were identified as putatively causal, highlighting WDR6, DALRD3, CTNND1 and genes in the MHC region. Tissue and single-cell enrichment analyses highlighted hippocampal and cortical excitatory neurons, along with D1- and D2-type dopamine receptor-containing medium spiny neurons, as playing a role in OCD risk. OCD displayed significant genetic correlations with 65 out of 112 examined phenotypes. Notably, it showed positive genetic correlations with all included psychiatric phenotypes, in particular anxiety, depression, anorexia nervosa, and Tourette syndrome, and negative correlations with a subset of the included autoimmune disorders, educational attainment, and body mass index.. This study marks a significant step toward unraveling its genetic landscape and advances understanding of OCD genetics, providing a foundation for future interventions to address this debilitating …

ObjectiveThere is a pronounced gap in knowledge regarding the polygenic underpinnings of youth bipolar disorder (BD). This study aimed to compare polygenic risk score (PRS) in youth with BD, youth at high clinical and/or familial risk for BD (HR), and controls.MethodParticipants include a total of 344 youth of European ancestry, ages 13-20 years old, including 136 youth with BD, 121 HR youth, and 87 controls. PRS for BD, schizophrenia (SCZ), major depressive disorder (MDD), or attention-deficit/hyperactivity disorder (ADHD) were constructed using independent genome-wide summary statistics from adult cohorts. Multinomial logistic regression was used to examine the association between each PRS and diagnostic status (BD vs. HR vs. controls). All genetic analyses controlled for age, sex, and 2 genetic principal components.ResultsBD group showed significantly higher BD-PRS than the control group (OR=1 …

The endogenous opioid system is thought to play an important role in mother-infant attachment. In infant rhesus macaques, variation in the μ-opioid receptor gene (OPRM1) is related to differences in attachment behavior that emerges following repeated separation from the mother; specifically, infants carrying at least one copy of the minor G allele of the OPRM1 C77G polymorphism show heightened and more persistent separation distress, as well as a pattern of increased contact-seeking behavior directed towards the mother during reunions (at the expense of affiliation with other group members). Research in adult humans has also linked the minor G allele of the analogous OPRM1 A118G polymorphism with greater interpersonal sensitivity. Adopting an interactionist approach, we examined whether OPRM1 A118G genotype and maternal (in)sensitivity are associated with child attachment style, predicting that …