Abstract:
:Complement receptor 1 (CR1) is an Alzheimer's disease (AD) susceptibility locus that also influences AD-related traits such as episodic memory decline and neuritic amyloid plaque deposition. We implemented a functional fine-mapping approach, leveraging intermediate phenotypes to identify functional variant(s) within the CR1 locus. Using 1709 subjects (697 deceased) from the Religious Orders Study and the Rush Memory and Aging Project, we tested 41 single-nucleotide polymorphisms (SNPs) within the linkage disequilibrium block containing the published CR1 AD SNP (rs6656401) for associations with episodic memory decline, and then examined the functional consequences of the top result. We report that a coding variant in the LHR-D (long homologous repeat D) region of the CR1 gene, rs4844609 (Ser1610Thr, minor allele frequency = 0.02), is associated with episodic memory decline and accounts for the known effect of the index SNP rs6656401 (D' = 1, r(2)= 0.084) on this trait. Further, we demonstrate that the coding variant's effect is largely dependent on an interaction with APOE-ε4 and mediated by an increased burden of AD-related neuropathology. Finally, in our data, this coding variant is also associated with AD susceptibility (joint odds ratio = 1.4). Taken together, our analyses identify a CR1 coding variant that influences episodic memory decline; it is a variant known to alter the conformation of CR1 and points to LHR-D as the functional domain within the CR1 protein that mediates the effect on memory decline. We thus implicate C1q and MBL, which bind to LHR-D, as likely targets of the variant's effect and suggest that CR1 may be an important intermediate in the clearance of Aβ42 particles by C1q.
journal_name
Hum Mol Genetjournal_title
Human molecular geneticsauthors
Keenan BT,Shulman JM,Chibnik LB,Raj T,Tran D,Sabuncu MR,Alzheimer's Disease Neuroimaging Initiative.,Allen AN,Corneveaux JJ,Hardy JA,Huentelman MJ,Lemere CA,Myers AJ,Nicholson-Weller A,Reiman EM,Evans DA,Bennett DA,De Jdoi
10.1093/hmg/dds054subject
Has Abstractpub_date
2012-05-15 00:00:00pages
2377-88issue
10eissn
0964-6906issn
1460-2083pii
dds054journal_volume
21pub_type
杂志文章abstract::Mitochondria undergo continuous cycles of fusion and fission in response to physiopathological stimuli. The key player in mitochondrial fission is dynamin-related protein 1 (DRP1), a cytosolic protein encoded by dynamin 1-like (DNM1L) gene, which relocalizes to the outer mitochondrial membrane, where it assembles, oli...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddz211
更新日期:2020-01-15 00:00:00
abstract::Angelman syndrome (AS) is a neurodevelopmental disorder caused due to deletions or loss-of-function mutations in maternally inherited UBE3A. Ube3a functions as an ubiquitin ligase as well as a transcriptional coactivator of steroid hormone receptors. However, the mechanisms by which maternal Ube3a deficiency gives ris...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddr614
更新日期:2012-04-15 00:00:00
abstract::Genetic polymorphisms are thought to play an important role in determining susceptibility to neural tube defects (NTDs), for example between different ethnic groups, but the embryonic manifestation of these polymorphic genetic influences is unclear. We have used a mouse model to test experimentally whether polymorphic...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/9.4.575
更新日期:2000-03-01 00:00:00
abstract::ARHI has been identified as a maternally imprinted tumor suppressor gene that maps to chromosome 1p31 and whose expression is markedly down-regulated in breast cancer. To explore possible mechanisms that could silence ARHI expression, we have tested the importance of DNA methylation, histone acetylation and histone me...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddg204
更新日期:2003-08-01 00:00:00
abstract::Genetic studies have implicated the neuronal ubiquitin C-terminal hydrolase (UCH) protein UCH-L1 in Parkinson's disease (PD) pathogenesis. Moreover, the function of UCH-L1 may be lost in the brains of PD and Alzheimer's disease patients. We have previously reported that the UCH-L1 polymorphic variant S18Y, potentially...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddr521
更新日期:2012-02-15 00:00:00
abstract::Mutations in S-phase cyclin A-associated protein in the endoplasmic reticulum (SCAPER) cause a recessively inherited multisystemic disorder whose main features are retinal degeneration and intellectual disability. SCAPER, originally identified as a cell cycle regulator, was also suggested to be a ciliary protein. Beca...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddaa113
更新日期:2020-08-03 00:00:00
abstract::Various small molecule pharmacologic agents with different known functions produce similar outcomes in diverse Mendelian and complex disorders, suggesting that they may induce common cellular effects. These molecules include histone deacetylase inhibitors, 4-phenylbutyrate (4PBA) and trichostatin A, and two small mole...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/dds247
更新日期:2012-10-01 00:00:00
abstract::Microdeletion at chromosomal position 15q13.3 has been described in intellectual disability, autism spectrum disorders, schizophrenia and recently in idiopathic generalized epilepsy (IGE). Using independent IGE cohorts, we first aimed to confirm the association of 15q13.3 deletions and IGE. We then set out to determin...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddp311
更新日期:2009-10-01 00:00:00
abstract::Biased segregation of mitochondrial DNA variants has been widely documented, but little was known about its molecular basis. We set out to test the hypothesis that altering the balance between mitochondrial fusion and fission could influence the segregation of mutant and wild-type mtDNA variants, because it would modi...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddp281
更新日期:2009-09-15 00:00:00
abstract::The group of dominant non-dystrophic myotonias, comprising disorders characterized by clinically similar forms of myogenic muscle stiffness, is genetically inhomogeneous. Dominant myotonia congenita (Thomsen's disease) is linked to CLCN1, the gene encoding the major muscle chloride channel, localized on chromosome 7q3...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/4.8.1397
更新日期:1995-08-01 00:00:00
abstract::Hearing loss is the most common sensory deficit in humans. We show that a point mutation in DCDC2 (DCDC2a), a member of doublecortin domain-containing protein superfamily, causes non-syndromic recessive deafness DFNB66 in a Tunisian family. Using immunofluorescence on rat inner ear neuroepithelia, DCDC2a was found to ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddv009
更新日期:2015-05-01 00:00:00
abstract::The minibrain (mnb) gene of Drosophila melanogaster encodes a serine-threonine protein kinase with an essential role in postembryonic neurogenesis. A corresponding human gene with similar function to mnb could provide important insights into both normal brain development and the abnormal brain development and mental r...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/5.9.1305
更新日期:1996-09-01 00:00:00
abstract::HTRA2-BETA1 is an SR-like protein that regulates alternative splice site selection in a concentration-dependent manner. Its proper concentration is important as several pathological states are associated with its change. We investigated the mechanism that controls the cellular HTRA2-BETA1 concentration and found it ut...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddh051
更新日期:2004-03-01 00:00:00
abstract::The EPM2A gene, encoding the dual-phosphatase laforin, is mutated in a fatal form of progressive myoclonus epilepsy known as Lafora disease (LD). The EPM2A gene, by differential splicing of its transcripts, is known to encode two laforin isoforms having distinct carboxyl termini; a major isoform localized in the cytop...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddn199
更新日期:2008-10-01 00:00:00
abstract::Germline mutations in LKB1 have been reported to underlie familial Peutz-Jeghers syndrome (PJS) with intestinal hamartomatous polyps and an elevated risk of various neoplasms. To investigate the prevalence of LKB1 germline mutations in PJS more generally, we studied samples from 33 unrelated PJS patients including eig...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/8.1.45
更新日期:1999-01-01 00:00:00
abstract::Mutations in PTEN-induced putative kinase 1 (PINK1) or parkin cause autosomal recessive forms of Parkinson disease (PD), but how these mutations trigger neurodegeneration is poorly understood and the exact functional relationship between PINK1 and parkin remains unclear. Here, we report that PINK1 regulates the E3 ubi...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddp501
更新日期:2010-01-15 00:00:00
abstract::Since recombinant adeno-associated virus (rAAV) was first described as a potential mammalian cell transducing system, frequent reports purportedly solving the problems of scalable production have appeared. Yet few of these processes have enabled the development of robust and economical rAAV production. Two production ...
journal_title:Human molecular genetics
pub_type: 杂志文章,评审
doi:10.1093/hmg/ddr141
更新日期:2011-04-15 00:00:00
abstract::Deletions within the neurexin 1 gene (NRXN1; 2p16.3) are associated with autism and have also been reported in two families with schizophrenia. We examined NRXN1, and the closely related NRXN2 and NRXN3 genes, for copy number variants (CNVs) in 2977 schizophrenia patients and 33 746 controls from seven European popula...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddn351
更新日期:2009-03-01 00:00:00
abstract::The RASopathies are a group of genetic syndromes caused by upregulated RAS signaling. Noonan syndrome (NS), the most common entity among the RASopathies, is characterized mainly by short stature, cardiac anomalies and distinctive facial features. Mutations in multiple RAS-MAPK pathway-related genes have been associate...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddz108
更新日期:2020-07-21 00:00:00
abstract::Cone photoreceptors (cones) are essential for high-resolution daylight vision and colour perception. Loss of cones in hereditary retinal diseases has a dramatic impact on human vision. The mechanisms underlying cone death are poorly understood, and consequently, there are no treatments available. Previous studies sugg...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddw219
更新日期:2016-09-01 00:00:00
abstract::Fragile X syndrome, a common cause of intellectual disability and autism, is due to mutational silencing of the FMR1 gene leading to the absence of its gene product, fragile X mental retardation protein (FMRP). FMRP is a selective RNA binding protein owing to two central K-homology domains and a C-terminal arginine-gl...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddu586
更新日期:2015-03-15 00:00:00
abstract::Two brothers presented with a clinical picture characterized by sideroblastic anemia, mild pancreatic insufficiency and progressive muscle weakness. The presence of an associated permanent basal lactic acidemia raised the suspicion of a mitochondrial disease. A muscle biopsy performed in both siblings proved the prese...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/3.11.1945
更新日期:1994-11-01 00:00:00
abstract::Multiple endocrine neoplasia type 2 (MEN 2) is a dominantly inherited cancer syndrome which affects thyroid C cells, and with variable frequency, the adrenal medulla, parathyroid and enteric autonomic ganglia. The syndrome is due to germline mutation in the receptor tyrosine kinase gene, RET. We have recently shown an...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/3.10.1771
更新日期:1994-10-01 00:00:00
abstract::Glomerular disease is one of the most common causes of end-stage renal failure. Increasing evidence suggests that these glomerulopathies are frequently caused by primary lesions in the renal podocytes. One of the major consequences of podocyte lesions is the accumulation of mesangial matrix in the glomerular basement ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/11.6.651
更新日期:2002-03-15 00:00:00
abstract::The near completeness of human chromosome sequences is facilitating accurate characterization and assessment of all classes of genomic variation. Particularly, using the DNA reference sequence as a guide, genome scanning technologies, such as microarray-based comparative genomic hybridization (array CGH) and genome-wi...
journal_title:Human molecular genetics
pub_type: 杂志文章,评审
doi:10.1093/hmg/ddl057
更新日期:2006-04-15 00:00:00
abstract::Lafora progressive myoclonus epilepsy, caused by defective laforin or malin, insidiously present in normal teenagers with cognitive decline, followed by rapidly intractable epilepsy, dementia and death. Pathology reveals neurodegeneration with neurofibrillary tangle formation and Lafora bodies (LBs). LBs are deposits ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddi306
更新日期:2005-09-15 00:00:00
abstract::We present the analysis of a prospective multicentre study to investigate genetic effects on the prognosis of newly treated epilepsy. Patients with a new clinical diagnosis of epilepsy requiring medication were recruited and followed up prospectively. The clinical outcome was defined as freedom from seizures for a min...
journal_title:Human molecular genetics
pub_type: 杂志文章,多中心研究
doi:10.1093/hmg/ddt403
更新日期:2014-01-01 00:00:00
abstract::Cigarette smoking is a leading modifiable cause of death worldwide. We hypothesized that cigarette smoking induces extensive transcriptomic changes that lead to target-organ damage and smoking-related diseases. We performed a meta-analysis of transcriptome-wide gene expression using whole blood-derived RNA from 10,233...
journal_title:Human molecular genetics
pub_type: 杂志文章,meta分析
doi:10.1093/hmg/ddw288
更新日期:2016-11-01 00:00:00
abstract::Cornelia de Lange syndrome (CdLS), which is reported to affect ∼1 in 10 000 to 30 000 newborns, is a multisystem organ developmental disorder with relatively mild to severe effects. Among others, intellectual disability represents an important feature of this condition. CdLS can result from mutations in at least five ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddy329
更新日期:2019-01-01 00:00:00
abstract::Wolf-Hirschhorn syndrome (WHS) is a complex congenital syndrome caused by a monoallelic deletion of the short arm of chromosome 4. Seizures in WHS have been associated with deletion of LETM1 gene. LETM1 encodes for the human homologue of yeast Mdm38p, a mitochondria-shaping protein of unclear function. Here we show th...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddm297
更新日期:2008-01-15 00:00:00