Author Correction: Loss of function of NCOR1 and NCOR2 impairs memory through a novel GABAergic hypothalamus-CA3 projection.

In the version of this article initially published, the Acknowledgements erroneously included a grant number that did not directly support the work in the article. The last sentence of the Acknowledgments should have read, "The authors' laboratories were supported by National Natural Science Foundation of China grants 31671222 and 31571556 (G.D.), a Taishan Scholarship (X.H.), the American Diabetes Association (ADA1-17-PDF-138) (Y.H.), the US Department of Agriculture (USDA) Cris6250-51000-059-04S (Y.X.), National Institutes of Health grants R01DK101379, R01DK117281, P01DK113954, R01DK115761 (Y.X.), the American Heart Association grant AHA30970064 (Z.S.), and grants R21CA215591 and R01ES027544 (Z.S.)." The error has been corrected in the HTML and PDF versions of the article.

Loss of function of NCOR1 and NCOR2 impairs memory through a novel GABAergic hypothalamus-CA3 projection.

Nuclear receptor corepressor 1 (NCOR1) and NCOR2 (also known as SMRT) regulate gene expression by activating histone deacetylase 3 through their deacetylase activation domain (DAD). We show that mice with DAD knock-in mutations have memory deficits, reduced anxiety levels, and reduced social interactions. Mice with NCOR1 and NORC2 depletion specifically in GABAergic neurons (NS-V mice) recapitulated the memory deficits and had reduced GABAA receptor subunit α2 (GABRA2) expression in lateral hypothalamus GABAergic (LHGABA) neurons. This was associated with LHGABA neuron hyperexcitability and impaired hippocampal long-term potentiation, through a monosynaptic LHGABA to CA3GABA projection. Optogenetic activation of this projection caused memory deficits, whereas targeted manipulation of LHGABA or CA3GABA neuron activity reversed memory deficits in NS-V mice. We describe de novo variants in NCOR1, NCOR2 or HDAC3 in patients with intellectual disability or neurodevelopmental disorders. These findings identify a hypothalamus-hippocampus projection that may link endocrine signals with synaptic plasticity through NCOR-mediated regulation of GABA signaling.

Circadian rhythm of homocysteine is hCLOCK genotype dependent.

Homocysteine (Hcy) is known to be a prognostic marker for neurological, cardiovascular and cerebrovascular diseases and several other pathophysiological conditions. A sudden surge in Hcy can increase cardiovascular events. Hemodynamic modulations are known to be associated with individual's chronotype. Therefore, precise monitoring of Hcy is crucial for evaluating its impact on risk. The aim of the present study was to investigate the rhythmicity of Hcy under controlled dietary conditions and whether this rhythmicity is under the genetic control of circadian rhythm. Five subjects were selected from 200 Malayalam speaking healthy ethnic individuals who were screened for functionally critical variants of MTHFR and hCLOCK genes. MTHFR is the rate-limiting enzyme in the methionine cycle and critical for regulating Hcy levels while hCLOCK is a critical gene responsible in regulating the day and night cycles. Rhythmicity in Hcy levels were observed in all the subjects with a consensus on a morning nadir and an evening peak. Gender specific stratification of Hcy levels were observed among similar genotypes of MTHFR and hCLOCK genes. Variations from the conventional rhythmicity of Hcy were observed among similar genotypes of MTHFR and dissimilar hCLOCK genotypes. A reduced plasma Hcy in hCLOCK rs1801260 CC genotype individuals were observed in contrast to CT genotype individuals. The study tends to suggest that Hcy and body time are genetically interdependent and throws light on some of the previously unexplained reasons for variability in Hcy levels. A population specific variation of MTHFR and hCLOCK genes also highlights ethnicity specific risk management.

Common variants on Xq28 conferring risk of schizophrenia in Han Chinese.

Schizophrenia is a highly heritable, severe psychiatric disorder affecting approximately 1% of the world population. A substantial portion of heritability is still unexplained and the pathophysiology of schizophrenia remains to be elucidated. To identify more schizophrenia susceptibility loci, we performed a genome-wide association study (GWAS) on 498 patients with schizophrenia and 2025 controls from the Han Chinese population, and a follow-up study on 1027 cases and 1005 controls. In the follow-up study, we included 384 single nucleotide polymorphisms (SNPs) which were selected from the top hits in our GWAS (130 SNPs) and from previously implicated loci for schizophrenia based on the SZGene database, NHGRI GWAS Catalog, copy number variation studies, GWAS meta-analysis results from the international Psychiatric Genomics Consortium (PGC) and candidate genes from plausible biological pathways (254 SNPs). Within the chromosomal region Xq28, SNP rs2269372 in RENBP achieved genome-wide significance with a combined P value of 3.98 × 10(-8) (OR of allele A = 1.31). SNPs with suggestive P values were identified within 2 genes that have been previously implicated in schizophrenia, MECP2 (rs2734647, P combined = 8.78 × 10(-7), OR = 1.28; rs2239464, P combined = 6.71 × 10(-6), OR = 1.26) and ARHGAP4 (rs2269368, P combined = 4.74 × 10(-7), OR = 1.25). In addition, the patient sample in our follow-up study showed a significantly greater burden for pre-defined risk alleles based on the SNPs selected than the controls. This indicates the existence of schizophrenia susceptibility loci among the SNPs we selected. This also further supports multigenic inheritance in schizophrenia. Our findings identified a new schizophrenia susceptibility locus on Xq28, which harbor the genes RENBP, MECP2, and ARHGAP4.