Evidence for genetic heterogeneity between clinical subtypes of bipolar disorder

Abstract

We performed a genome-wide association study of 6447 bipolar disorder (BD) cases and 12 639 controls from the International Cohort Collection for Bipolar Disorder (ICCBD). Meta-analysis was performed with prior results from the Psychiatric Genomics Consortium Bipolar Disorder Working Group for a combined sample of 13 902 cases and 19 279 controls. We identified eight genome-wide significant, associated regions, including a novel associated region on chromosome 10 (rs10884920; P=3.28 × 10−8) that includes the brain-enriched cytoskeleton protein adducin 3 (ADD3), a non-coding RNA, and a neuropeptide-specific aminopeptidase P (XPNPEP1). Our large sample size allowed us to test the heritability and genetic correlation of BD subtypes and investigate their genetic overlap with schizophrenia and major depressive disorder. We found a significant difference in heritability of the two most common forms of BD (BD I SNP-h2=0.35; BD II SNP-h2=0.25; P=0.02). The genetic correlation between BD I and BD II was 0.78, whereas the genetic correlation was 0.97 when BD cohorts containing both types were compared. In addition, we demonstrated a significantly greater load of polygenic risk alleles for schizophrenia and BD in patients with BD I compared with patients with BD II, and a greater load of schizophrenia risk alleles in patients with the bipolar type of schizoaffective disorder compared with patients with either BD I or BD II. These results point to a partial difference in the genetic architecture of BD subtypes as currently defined.

Probing the lithium-response pathway in hiPSCs implicates the phosphoregulatory set-point for a cytoskeletal modulator in bipolar pathogenesis

“…Additionally, axonal guidance signaling appeared most centralized; its function connected with 75% of the pathways identified in the IPA analysis. Of the 15 candidate protein targets, the one most pivotal to axonal guidance and cytoskeletal dynamics was CRMP2, originally discovered as the mediator of Sema3A's (initially named "collapsin") guidance of neurite extension and axonal growth cone development (5)(6)(7)(8)(9)(10)(11).…”

“…Two obstacles to developing safer, more effective mood stabilizers have been a lack of known clinically relevant molecular drug targets and of drug-screening assays that are rooted in the molecular pathogenesis and pathophysiology of the disorder. Although heritability of BPD is ∼80%, few disease-specific gene associations have been identified with sufficient consistency and statistical significance to guide further studies (9,10); multiple loci are more likely to contribute to LiR than any single reliable genetic marker, making it challenging for hiPSC disease-modeling technology. The approach presented here might help address these challenges.…”

Recent Genetics and Epigenetics Approaches to PTSD

“…For example, one might consider grouping individuals on the basis of the presence of manic or psychotic episodes, rather than schizophrenia and bipolar disorder diagnoses [66]. These types of analyses have already been successful in studying shared genetic risk of bipolar disorder and schizophrenia [67, 68]. This approach can also be applied to PTSD that is comorbid with depression, traumatic brain injury, and a variety of psychiatric conditions [2•, 69] and physical health conditions [70].…”

Sequence Analysis of Drug Target Genes with Suicidal Behavior in Bipolar Disorder Patients

“…Furthermore, our discovery and replication samples may differ in the proportion of patients with bipolar I disorder versus bipolar II disorder. The recently reported incomplete genetic correlation between bipolar I and bipolar II disorders and the potentially different risk factors of suicidal behavior between bipolar I and bipolar II disorders could explain the lack of substantial replication for the majority of our findings [38, 39]. Furthermore, we did not have detailed information on alcohol use, which might have contributed to the mixed findings.…”