Abstract:
:To identify genes that affect body mass index (BMI) in American Indians who are predominately of Pima Indian heritage, we previously completed a genome-wide association study in 1120 American Indians. That study also included follow-up genotyping for 9 SNPs in 2133 additional subjects. A comprehensive follow-up study has subsequently been completed where 292 SNPs were genotyped in 3562 subjects, of which 128 SNPs were assessed for replication in 3238 additional subjects. In the combined subjects (n = 6800), BMI associations for two SNPs, rs12882548 and rs11652094, approached genome-wide significance (P = 6.7 × 10(-7) and 8.1 × 10(-7), respectively). Rs12882548 is located in a gene desert on chromosome 14 and rs11652094 maps near MAP2K3. Several SNPs in the MAP2K3 region including rs11652094 were also associated with BMI in Caucasians from the GIANT consortium (P = 10(-2)-10(-5)), and the combined P-values across both American Indians and Caucasian were P = 10(-4)-10(-9). Follow-up sequencing across MAP2K3 identified several paralogous sequence variants indicating that the region may have been duplicated. MAP2K3 expression levels in adipose tissue biopsies were positively correlated with BMI, although it is unclear if this correlation is a cause or effect. In vitro studies with cloned MAP2K3 promoters suggest that MAP2K3 expression may be up-regulated during adipogenesis. Microarray analyses of mouse hypothalamus cells expressing constitutively active MAP2K3 identified several up-regulated genes involved in immune/inflammatory pathways and a gene, Hap1, thought to play a role in appetite regulation. We conclude that MAP2K3 is a reproducible obesity locus that may affect body weight via complex mechanisms involving appetite regulation and hypothalamic inflammation.
journal_name
Hum Mol Genetjournal_title
Human molecular geneticsauthors
Bian L,Traurig M,Hanson RL,Marinelarena A,Kobes S,Muller YL,Malhotra A,Huang K,Perez J,Gale A,Knowler WC,Bogardus C,Baier LJdoi
10.1093/hmg/ddt291subject
Has Abstractpub_date
2013-11-01 00:00:00pages
4438-49issue
21eissn
0964-6906issn
1460-2083pii
ddt291journal_volume
22pub_type
杂志文章abstract::DiGeorge syndrome is a human developmental disorder resulting in hypoplasia of the thymus and parathyroids, and conotruncal heart defects. We recently isolated four genes with zinc finger DNA binding motifs mapping to chromosome 22q11.2 DiGeorge critical region. We now report that one of them, ZNF74 gene, is hemizygou...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/2.10.1583
更新日期:1993-10-01 00:00:00
abstract::The internal structure of different alleles of the minisatellite present at the 3' end of the apolipoprotein B (ApoB) gene has been analysed by different approaches including sequencing. The repeat unit arrangements of the minisatellite on 570 chromosomes belonging to European and African populations were thus determi...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/5.1.61
更新日期:1996-01-01 00:00:00
abstract::Histamine (HA) acts as a neurotransmitter in the brain, which participates in the regulation of many biological processes including inflammation, gastric acid secretion and neuromodulation. The enzyme histamine N-methyltransferase (HNMT) inactivates HA by transferring a methyl group from S-adenosyl-l-methionine to HA,...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddv286
更新日期:2015-10-15 00:00:00
abstract::The oculo-auriculo-vertebral spectrum (OAVS) (OMIM % 164210) is a common developmental disorder characterized by hemifacial microsomia, epibulbar tumours, ear malformation and vertebral anomalies. Although rare familial cases suggest that OAVS has a genetic basis, no genetic defect has been identified so far. In a pat...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddi474
更新日期:2006-02-15 00:00:00
abstract::Hand-Foot-Genital syndrome is a rare condition caused by mutations in the HOXA13 gene and characterized by limb malformations and urogenital defects. While the role of Hoxa13 in limb development has been extensively studied, its function during the development of the urogenital system remains elusive mostly due to the...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddz013
更新日期:2019-05-15 00:00:00
abstract::Rett syndrome (RTT) is a neurodevelopmental disorder with no efficient treatment that is caused in the majority of cases by mutations in the gene methyl-CpG binding-protein 2 (MECP2). RTT becomes manifest after a period of apparently normal development and causes growth deceleration, severe psychomotor impairment and ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddq563
更新日期:2011-03-15 00:00:00
abstract::Identification of genes associated with pain insensitivity syndromes can increase the understanding of the pathways involved in pain and contribute to the understanding of how sensory pathways relate to other neurological functions. In this report we describe the mapping and identification of the gene responsible for ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddh096
更新日期:2004-04-15 00:00:00
abstract::Genomic DNA from 19 Japanese patients with congenital lipoid adrenal hyperplasia (lipoid CAH) representing 16 different families was examined to identify the genetic alterations of steroidogenic acute regulatory protein (StAR). Ten of 19 patients had a 46,XX karyotype and nine had a 46,XY karyotype. Six of the 46,XX p...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/6.4.571
更新日期:1997-04-01 00:00:00
abstract::The success of the human genome sequencing project has created wide-spread interest in exploring the human epigenome in order to elucidate how the genome executes the information it holds. Although all (nucleated) human cells effectively contain the same genome, they contain very different epigenomes depending upon ce...
journal_title:Human molecular genetics
pub_type: 杂志文章,评审
doi:10.1093/hmg/ddi110
更新日期:2005-04-15 00:00:00
abstract::Uromodulin (UMOD) mutations are responsible for three autosomal dominant tubulo-interstitial nephropathies including medullary cystic kidney disease type 2 (MCKD2), familial juvenile hyperuricemic nephropathy and glomerulocystic kidney disease. Symptoms include renal salt wasting, hyperuricemia, gout, hypertension and...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddq077
更新日期:2010-05-15 00:00:00
abstract::Hay-Wells syndrome, also known as ankyloblepharon-ectodermal dysplasia-clefting (AEC) syndrome (OMIM 106260), is a rare autosomal dominant disorder characterized by congenital ectodermal dysplasia, including alopecia, scalp infections, dystrophic nails, hypodontia, ankyloblepharon and cleft lip and/or cleft palate. Th...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/10.3.221
更新日期:2001-02-01 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
abstract::Immunoglobulin E (IgE) concentration in serum is elevated in atopic diseases such as asthma. A large genomic region on chromosome 5 has previously been implicated in the control of IgE levels and bronchial hyperreactivity and may, therefore, harbor genes predisposing to asthma. In an effort to confirm this linkage and...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/6.12.2069
更新日期:1997-11-01 00:00:00
abstract::Autosomal dominant polycystic kidney disease (ADPKD) is among the most common monogenic disorders mainly associated with PKD1/PC1 mutations. We show herein that renal regulation in Pc1 dosage-reduced and -increased mouse models converge toward stimulation of c-Myc expression along with β-catenin, delineating c-Myc as ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddy379
更新日期:2019-03-01 00:00:00
abstract::Junctional epidermolysis bullosa inversa is an autosomal recessive blistering skin disease with an ultrastructural hemidesmosome defect similar to that of the Herlitz disease, yet with a non-lethal and different course of the disease. Its delineation is based on five geographically associated Norwegian families where ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/3.8.1387
更新日期:1994-08-01 00:00:00
abstract::Spinal muscular atrophy (SMA) is the most common genetic cause of infant mortality. SMA is caused by loss of functional survival motor neuron 1 (SMN1), resulting in death of spinal motor neurons. Current therapeutic research focuses on modulating the expression of a partially functioning copy gene, SMN2, which is reta...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddn426
更新日期:2009-03-15 00:00:00
abstract::Mendelian susceptibility to mycobacterial disease (MSMD) is characterized by clinical disease caused by weakly virulent mycobacteria, such as environmental mycobacteria and Bacillus Calmette-Guérin vaccines, in otherwise healthy individuals. All known genetic etiologies disrupt interferon (IFN)-γ immunity. Germline bi...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddy275
更新日期:2018-11-15 00:00:00
abstract::Mutations in subunits or regulators of cohesin cause a spectrum of disorders in humans known as the 'cohesinopathies'. Cohesinopathies, including the best known example Cornelia de Lange syndrome (CdLS), are characterized by broad spectrum, multifactorial developmental anomalies. Heart defects occur at high frequency ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddv402
更新日期:2015-12-15 00:00:00
abstract::Dyskeratosis congenita (DC) is a rare genetic syndrome that gives rise to a variety of disorders in affected individuals. Remarkably, all causative gene mutations identified to date share a link to telomere/telomerase biology. We found that the most prevalent dyskerin mutation in DC (A353V) did not affect formation of...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddp551
更新日期:2010-03-01 00:00:00
abstract::Eukaryotic elongation factor 1A (EEF1A), is encoded by two distinct isoforms, EEF1A1 and EEF1A2; whereas EEF1A1 is expressed almost ubiquitously, EEF1A2 expression is limited such that it is only detectable in skeletal muscle, heart, brain and spinal cord. Currently, the role of EEF1A2 in normal cardiac development an...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddx239
更新日期:2017-09-15 00:00:00
abstract::Lysosomal neuraminidase is the key enzyme for the intralysosomal catabolism of sialylated glycoconjugates and is deficient in two neurodegenerative lysosomal disorders, sialidosis and galactosialidosis. Here we report the identification of eight novel mutations in the neuraminidase gene of 11 sialidosis patients with ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/9.18.2715
更新日期:2000-11-01 00:00:00
abstract::Hypomorphic mutations of the MRE11 gene are the hallmark of the radiosensitive ataxia-telangiectasia-like disorder (ATLD). Here, we describe a new family with two affected siblings, ATLD5 and ATLD6, now aged 37 and 36, respectively. They presented with late onset cerebellar degeneration slowly progressing until pubert...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddh221
更新日期:2004-09-15 00:00:00
abstract::Genome-wide association studies of colorectal cancer (CRC) have identified a number of common variants associated with modest risk, including rs3802842 at chromosome 11q23.1. Several genes map to this region but rs3802842 does not map to any known transcribed or regulatory sequences. We reasoned, therefore, that rs380...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddt584
更新日期:2014-04-15 00:00:00
abstract::Actinic keratosis (AK) is a pre-malignant skin disease, highly prevalent in elderly Europeans. This study investigates genetic susceptibility to AK with a genome-wide association study (GWAS). A full body skin examination was performed in 3194 elderly individuals from the Rotterdam Study (RS) of exclusive north-wester...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddv076
更新日期:2015-06-01 00:00:00
abstract::Multiple mitochondrial DNA deletions are associated with clinically heterogeneous disorders transmitted as mendelian traits. Dominant missense mutations were found in the gene encoding the heart and skeletal muscle-specific isoform of the adenine nucleotide translocator (ANT1) in families with autosomal dominant progr...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddi341
更新日期:2005-10-15 00:00:00
abstract::Recent prospective analysis identified secretory phospholipase A(2)-IIa (sPLA(2)IIa) as a coronary artery disease (CAD) risk predictor. This study aimed to examine the relationship between serum levels of sPLA(2)IIa and variation in the sPLA(2)IIa gene (PLA2G2A) in a cohort of patients with Type II diabetes (T2D) mell...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddi453
更新日期:2006-01-15 00:00:00
abstract::A relationship between fragile sites, specific genomic regions visible as gaps or breaks on cultivated chromosomes, and human disease has been proposed many years ago. Evidence for a role of the ubiquitously expressed common fragile sites characterized by peculiar genome architecture in cancer has been accumulated ove...
journal_title:Human molecular genetics
pub_type: 杂志文章,评审
doi:10.1093/hmg/ddm136
更新日期:2007-10-15 00:00:00
abstract::Acetazolamide responsive hereditary paroxysmal cerebellar ataxia (APCA) is a rare autosomal dominant disorder characterized by attacks of cerebellar ataxia and dysarthria with normal or near normal neurologic function between attacks. A genome-wide search using polymorphic di- and tri-nucleotide repeats was initiated ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/4.2.279
更新日期:1995-02-01 00:00:00
abstract::Pheochromocytomas (PCCs) and paragangliomas (PGLs) are chromaffin-cell tumors that arise from the adrenal medulla and extra-adrenal paraganglia, respectively. The dysfunction of genes involved in the cellular response to hypoxia, such as VHL, EGL nine homolog 1, and the succinate dehydrogenase (SDH) genes, leads to a ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddt069
更新日期:2013-06-01 00:00:00
abstract::CHARGE syndrome is a multiple congenital anomaly disorder that leads to life-threatening birth defects, such as choanal atresia and cardiac malformations as well as multiple sensory impairments, that affect hearing, vision, olfaction and balance. CHARGE is caused by heterozygous mutations in CHD7, which encodes an ATP...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddt435
更新日期:2014-01-15 00:00:00