Evidence for genetic heterogeneity between clinical subtypes of bipolar disorder.

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.

Subtle developmental abnormalities in the inferior olive: an indicator of prenatal brainstem injury in the sudden infant death syndrome.

Subtle quantitative abnormalities in neuronal populations derived from the rhombic lip (i.e. arcuate nucleus at the ventral medullary surface, external granular layer of the cerebellum) have been reported in victims of the sudden infant death syndrome (SIDS). In this study, we examined the inferior olive, a major rhombic lip derivative, to determine if subtle rhombic lip abnormalities also involve this nucleus in SIDS. We analyzed the number and density of neurons and reactive astrocytes in the inferior olive in 29 SIDS cases and 29 controls. Computer-assisted cell counting procedures were used in sections stained with hematoxylin and eosin/Luxol fast blue. There was a significant difference in the postconceptionally age-adjusted mean for neuronal density between SIDS cases (7,687 +/- 255 neurons/mm(3)) and controls (8,889 +/- 255 neurons/mm(3)) (p = 0.002). The difference in age-adjusted mean neuronal number between SIDS cases (1,932 +/- 89 neurons/2 sections) and controls (2,172 +/- 89 neurons/2 sections) was marginally significant (p = 0.063). Reactive astrocytes were present in the inferior olive in SIDS cases, but their number, density, and developmental profile were not significantly different from that of control infants dying of diverse known causes. SIDS victims found dead in cribs, beds, and sofas, prone or supine had subtle olivary abnormalities, suggesting that affected infants are at risk in various sleeping situations. We propose that at least some SIDS victims experience intrauterine brainstem injury including the olivo-arcuato-cerebellar circuitry derived from the rhombic lip. These observations provide future directions for SIDS research concerning the role of early insults in pregnancy, the rhombic lip, and the interactions of the ventral medulla and cerebellum in cardioventilatory control.