Biology subjects
Borglum, A. D.
Publications and source records attributed to Borglum, A. D..
The behavioral and neurobiological effects of reduced Brd1 expression in mice are sex-biased and implicate gender dependent dysregulation of nuclear receptor mediated signaling in mental disorders
The schizophrenia and bipolar disorder associated gene, BRD1, encodes a scaffold protein that in complex with epigenetic modifiers regulate gene sets enriched for psychiatric disorder risk. Preclinical evidence from male Brd1+/- mice has previously implicated BRD1 with phenotypes of translational relevance to schizophrenia. Here we describe the phenotype of female Brd1+/- mice and report attenuated dendritic architecture and monoaminergic dysregulation accompanied by sex-specific changes in affective behaviors. In accordance, global gene expression profiling reveals regional dysregulation of gene sets enriched with major depressive disorder and schizophrenia risk in female and male Brd1+/- mice, respectively. Independent of sex, however, differentially expressed genes cluster in common functional pathways associated with psychiatric disorders, including mitochondrial dysfunction and oxidative phosphorylation as well as G-protein coupled-, and nuclear receptor mediated signaling. Accordingly, we provide in vitro evidence that BRD1 modulates the transcriptional drive of a subset of nuclear receptors (e.g. the vitamin D and glucocorticoid receptors). Moreover, we demonstrate enrichment of psychiatric disorder risk in the target genes of nuclear receptors, sex-biased expression of several nuclear receptor genes in the adult brain of Brd1+/- mice, and that sex-biased genes in general are enriched with nuclear receptor genes particularly at the earliest developmental stage of the human brain. Overall, our data suggests that the spatio-temporal interaction between BRD1 and subsets of nuclear receptors in the brain is sex-biased and that hampered BRD1 mediated regulation of target genes governed by certain nuclear receptors may significantly contribute to sex differences in psychopathology.
Genome-wide association study implicates CHRNA2 in cannabis use disorder
Introductory paragraphCannabis is the most frequently used illicit psychoactive substance worldwide1. Life time use has been reported among 35-40% of adults in Denmark2 and the United States3. Cannabis use is increasing in the population4-6 and among users around 9% become dependent7. The genetic risk component is high with heritability estimates of 518-70%9. Here we report the first genome-wide significant risk locus for cannabis use disorder (CUD, P=9.31x10-12) that replicates in an independent population (Preplication=3.27x10-3, Pmetaanalysis=9.09x10-12). The finding is based on a genome-wide association study (GWAS) of 2,387 cases and 48,985 controls followed by replication in 5,501 cases and 301,041 controls. The index SNP (rs56372821) is a strong eQTL for CHRNA2 and analyses of the genetic regulated gene expressions identified significant association of CHRNA2 expression in cerebellum with CUD. This indicates a potential therapeutic use in CUD of compounds with agonistic effect on the neuronal acetylcholine receptor alpha-2 subunit encoded by CHRNA2. At the polygenic level analyses revealed a significant decrease in the risk of CUD with increased load of variants associated with cognitive performance.
Genetic markers of ADHD-related variations in intracranial volume
Attention-Deficit/Hyperactivity Disorder (ADHD) is a common and highly heritable neurodevelopmental disorder with a complex pathophysiology, where genetic risk is hypothesized to be mediated by alterations in structure and function of diverse brain networks. We tested one aspect of this hypothesis by investigating the genetic overlap between ADHD (n=55,374) and (mainly subcortical) brain volumes (n=11,221-24,704), using the largest publicly available studies. At the level of common variant genetic architecture, we discovered a significant negative genetic correlation between ADHD and intracranial volume (ICV). Meta-analysis of individual variants found significant loci associated with both ADHD risk and ICV; additional loci were identified for ADHD and amygdala, caudate nucleus, and putamen volumes. Gene-set analysis in the ADHD-ICV meta-analytic data showed significant association with variation in neurite outgrowth-related genes. In summary, our results suggest new hypotheses about biological mechanisms involved in ADHD etiology and highlight the need to study additional brain parameters.
A genetic investigation of sex bias in the prevalence of attention deficit hyperactivity disorder
Attention-deficit/hyperactivity disorder (ADHD) shows substantial heritability and is 2-7 times more common in males than females. We examined two putative genetic mechanisms underlying this sex bias: sex-specific heterogeneity and higher burden of risk in female cases. We analyzed genome-wide common variants from the Psychiatric Genomics Consortium and iPSYCH Project (20,183 cases, 35,191 controls) and Swedish population-registry data (N=77,905 cases, N=1,874,637 population controls). We find strong genetic correlation for ADHD across sex and no mean difference in polygenic burden across sex. In contrast, siblings of female probands are at an increased risk of ADHD, compared to siblings of male probands. The results also suggest that females with ADHD are at especially high risk of comorbid developmental conditions. Overall, this study supports a greater familial burden of risk in females with ADHD and some clinical and etiological heterogeneity. However, autosomal common variants largely do not explain the sex bias in ADHD prevalence.