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.
Subject(s)
Bipolar Disorder/genetics , Psychotic Disorders/genetics , Aminopeptidases/genetics , Ankyrins/genetics , Bipolar Disorder/classification , Bipolar Disorder/psychology , Calcium Channels, L-Type/genetics , Calmodulin-Binding Proteins/genetics , Case-Control Studies , Chromosomes, Human, Pair 10/genetics , Cytoskeletal Proteins , Genome-Wide Association Study , Genotype , Humans , Nerve Tissue Proteins/genetics , Nuclear Proteins/genetics , Phenotype , Polymorphism, Single Nucleotide , Psychotic Disorders/psychologyABSTRACT
Novel or atypical antipsychotic medications appear to offer patients the benefits of conventional neuroleptics with lower risks of side effects, but the newer drugs cost much more than the older drugs. Many U.S. psychiatrists have concluded that the novel antipsychotic drugs should be first-line therapy and represent an emerging standard of care in treating psychoses. This view raises the question of whether doctors who prescribe the older, cheaper drugs are engaging in malpractice or violating patients' rights. The authors explore reasons why psychiatrists may continue treating some psychotic patients with conventional neuroleptics, despite the apparent advantages of novel antipsychotics. They also describe possible sources of liability that might arise from using conventional neuroleptics and examine how existing case law might bear on these matters. Recent data on antipsychotic prescription practices and court decisions issued through September 2000 suggest that proper use of the older drugs is not a deviation from the standard of care. However, case law suggests that psychiatrists have a legal obligation to tell patients about novel antipsychotic agents even if they continue to prescribe conventional neuroleptics.
