| 1 | Mol. Psychiatry 2007 Nov 12: 1011-25 |
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| PMID | 17457313 |
| Title | Association analysis of the chromosome 4p15-p16 candidate region for bipolar disorder and schizophrenia. |
| Abstract | Several independent linkage studies have identified chromosome 4p15-p16 as a putative region of susceptibility for bipolar disorder (BP), schizophrenia (SCZ) and related phenotypes. Previously, we identified two subregions (B and D) of the 4p15-p16 region that are shared by three of four 4p-linked families examined. Here, we describe a large-scale association analysis of regions B and D (3.8 and 4.5 Mb, respectively). We selected 408 haplotype-tagging single nucleotide polymorphisms (SNPs) on a block-by-block basis from the International HapMap project and tested them in 368 BP, 386 SCZ and 458 control individuals. Nominal significance thresholds were determined using principal component analysis as implemented in the program SNPSpD. In region B, overlapping SNPs and haplotypes met the region-wide threshold (PPPARGC1A, mapped nearby. There were also nine other clusters within regions B and D with nominally significant haplotypes, but only at the individual haplotype level. KIAA0746, PPARGC1A, GPR125, CCKAR and DKFZp761B107 overlapped with these regions. This study has identified significant associations between BP and SCZ within the chromosome 4p linkage region, resulting in candidate regions worthy of further investigation. |
| SCZ Keywords | schizophrenia |
| 2 | J. Neurosci. 2014 Oct 34: 14375-87 |
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| PMID | 25339750 |
| Title | PGC-1? provides a transcriptional framework for synchronous neurotransmitter release from parvalbumin-positive interneurons. |
| Abstract | Accumulating evidence strongly implicates the transcriptional coactivator peroxisome proliferator-activated receptor ? coactivator 1? (PGC-1?) in the pathophysiology of multiple neurological disorders, but the downstream gene targets of PGC-1? in the brain have remained enigmatic. Previous data demonstrate that PGC-1? is primarily concentrated in inhibitory neurons and that PGC-1? is required for the expression of the interneuron-specific Ca(2+)-binding protein parvalbumin (PV) throughout the cortex. To identify other possible transcriptional targets of PGC-1? in neural tissue, we conducted a microarray on neuroblastoma cells overexpressing PGC-1?, mined results for genes with physiological relevance to interneurons, and measured cortical gene and protein expression of these genes in mice with underexpression and overexpression of PGC-1?. We observed bidirectional regulation of novel PGC-1?-dependent transcripts spanning synaptic [synaptotagmin 2 (Syt2) and complexin 1 (Cplx1)], structural [neurofilament heavy chain (Nefh)], and metabolic [neutral cholesterol ester hydrolase 1 (Nceh1), adenylate kinase 1 (Ak1), inositol polyphosphate 5-phosphatase J (Inpp5j), ATP synthase mitochondrial F1 complex O subunit (Atp5o), phytanol-CoA-2hydroxylase (Phyh), and ATP synthase mitrochondrial F1 complex ? subunit 1 (Atp5a1)] functions. The neuron-specific genes Syt2, Cplx1, and Nefh were developmentally upregulated in an expression pattern consistent with that of PGC-1? and were expressed in cortical interneurons. Conditional deletion of PGC-1? in PV-positive neurons significantly decreased cortical transcript expression of these genes, promoted asynchronous GABA release, and impaired long-term memory. Collectively, these data demonstrate that PGC-1? is required for normal PV-positive interneuron function and that loss of PGC-1? in this interneuron subpopulation could contribute to cortical dysfunction in disease states. |
| SCZ Keywords | schizophrenia |