Abstract:
:The identification of multiple signals at individual loci could explain additional phenotypic variance ('missing heritability') of common traits, and help identify causal genes. We examined gene expression levels as a model trait because of the large number of strong genetic effects acting in cis. Using expression profiles from 613 individuals, we performed genome-wide single nucleotide polymorphism (SNP) analyses to identify cis-expression quantitative trait loci (eQTLs), and conditional analysis to identify second signals. We examined patterns of association when accounting for multiple SNPs at a locus and when including additional SNPs from the 1000 Genomes Project. We identified 1298 cis-eQTLs at an approximate false discovery rate 0.01, of which 118 (9%) showed evidence of a second independent signal. For this subset of 118 traits, accounting for two signals resulted in an average 31% increase in phenotypic variance explained (Wilcoxon P< 0.0001). The association of SNPs with cis gene expression could increase, stay similar or decrease in significance when accounting for linkage disequilibrium with second signals at the same locus. Pairs of SNPs increasing in significance tended to have gene expression increasing alleles on opposite haplotypes, whereas pairs of SNPs decreasing in significance tended to have gene expression increasing alleles on the same haplotypes. Adding data from the 1000 Genomes Project showed that apparently independent signals could be potentially explained by a single association signal. Our results show that accounting for multiple variants at a locus will increase the variance explained in a substantial fraction of loci, but that allelic heterogeneity will be difficult to define without resequencing loci and functional work.
journal_name
Hum Mol Genetjournal_title
Human molecular geneticsauthors
Wood AR,Hernandez DG,Nalls MA,Yaghootkar H,Gibbs JR,Harries LW,Chong S,Moore M,Weedon MN,Guralnik JM,Bandinelli S,Murray A,Ferrucci L,Singleton AB,Melzer D,Frayling TMdoi
10.1093/hmg/ddr328subject
Has Abstractpub_date
2011-10-15 00:00:00pages
4082-92issue
20eissn
0964-6906issn
1460-2083pii
ddr328journal_volume
20pub_type
杂志文章abstract::TMEM70, a 21-kDa protein localized in the inner mitochondrial membrane, has been shown to facilitate the biogenesis of mammalian F1Fo ATP synthase. Mutations of the TMEM70 gene represent the most frequent cause of isolated ATP synthase deficiency resulting in a severe mitochondrial disease presenting as neonatal encep...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddw295
更新日期:2016-11-01 00:00:00
abstract::Fanconi anaemia (FA) is an autosomal recessive genetic disorder characterized by progressive bone marrow failure, multiple congenital abnormalities, and an increased risk of cancer. FA cells are characterized by chromosomal instability and hypersensitivity to DNA interstrand crosslinking agents. At least eight complem...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddg266
更新日期:2003-10-01 00:00:00
abstract::Superovulation or ovarian stimulation is currently an indispensable assisted reproductive technology (ART) for human subfertility/infertility treatment. Recently, increased frequencies of imprinting disorders have been correlated with ARTs. Significantly, for Angelman and Beckwith-Wiedemann Syndromes, patients have be...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddp465
更新日期:2010-01-01 00:00:00
abstract::Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disorder caused by a polyglutamine-encoding CAG repeat expansion in the ATXN3 gene. This expansion leads to misfolding and aggregation of mutant ataxin-3 (ATXN3) and degeneration of select brain regions. A key unanswered question in SCA3 and other polyglutami...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddx224
更新日期:2017-09-01 00:00:00
abstract::Circletail is one of only two mouse mutants that exhibit the most severe form of neural tube defect (NTD), termed craniorachischisis. In this disorder, almost the entire brain and spinal cord is affected, owing to a failure to initiate neural tube closure. Craniorachischisis is a significant cause of lethality in huma...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddg014
更新日期:2003-01-15 00:00:00
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journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddg041
更新日期:2003-02-15 00:00:00
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journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddh014
更新日期:2004-01-15 00:00:00
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journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/3.6.931
更新日期:1994-06-01 00:00:00
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journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddy235
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journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddn386
更新日期:2009-02-15 00:00:00
abstract::PTEN-induced putative kinase 1 (PINK1) and Parkin act in a common pathway to regulate mitochondrial dynamics, the involvement of which in the pathogenesis of Parkinson's disease (PD) is increasingly being appreciated. However, how the PINK1/Parkin pathway influences mitochondrial function is not well understood, and t...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddr235
更新日期:2011-08-15 00:00:00
abstract::Gene therapy holds great promise for curing Duchenne muscular dystrophy (DMD), the most common fatal inherited childhood muscle disease. Success of DMD gene therapy depends upon functional improvement in both skeletal and cardiac muscle. Numerous gene transfer studies have been performed to correct skeletal muscle pat...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddh174
更新日期:2004-08-01 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
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journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/7.5.855
更新日期:1998-05-01 00:00:00
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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
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journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddl148
更新日期:2006-07-15 00:00:00
abstract::Trinucleotide repeats at five disease loci (DM, DRPLA, HD, SBMA and SCA1) were surveyed in phenotypically normal individuals from three continental populations. This is the first analysis to examine the population dynamics of these five disease-related trinucleotide repeats in the same individuals from worldwide popul...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/4.9.1485
更新日期:1995-09-01 00:00:00
abstract::Insulin-like growth factor II (IGF-II) is a mitogen for many cell types and an important modulator of muscle growth and differentiation. IGF-II gene is prevalently expressed during prenatal development and its gene activity is regulated by genomic imprinting, in that the allele inherited from the father is active and ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/3.7.1117
更新日期:1994-07-01 00:00:00
abstract::Recent genome-wide association studies (GWAS) and subsequent meta-analyses have identified over 25 SNPs at 18 loci, together accounting for >15% of the genetic susceptibility to testicular germ cell tumour (TGCT). To identify further common SNPs associated with TGCT, here we report a three-stage experiment, involving ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddu511
更新日期:2015-02-15 00:00:00
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journal_title:Human molecular genetics
pub_type: 杂志文章,评审
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更新日期:2001-04-01 00:00:00
abstract::Serum total immunoglobulin E (IgE) is a critical intermediate phenotype of allergic diseases. Although total IgE exhibits sexual dimorphism in humans (with males demonstrating higher IgE than females), the molecular basis of this difference is unknown. A genome-wide scan of 380 short-tandem repeat (STR) markers was pe...
journal_title:Human molecular genetics
pub_type: 杂志文章
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更新日期:2007-02-01 00:00:00
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journal_title:Human molecular genetics
pub_type: 杂志文章
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更新日期:2016-06-15 00:00:00
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journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/10.2.127
更新日期:2001-01-15 00:00:00
abstract::Duchenne muscular dystrophy (DMD) is a devastating X-linked disease affecting ~1 in 5000 males. DMD patients exhibit progressive muscle degeneration and weakness, leading to loss of ambulation and premature death from cardiopulmonary failure. We previously reported that mouse Laminin-111 (msLam-111) protein could redu...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddz086
更新日期:2019-08-15 00:00:00
abstract::Missing teeth (hypodontia and oligodontia) are a common developmental abnormality in humans and heterozygous mutations of PAX9 have recently been shown to underlie a number of familial, non-syndromic cases. Whereas PAX9 haploinsufficiency has been suggested as the underlying genetic mechanism, it is not known how this...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddi388
更新日期:2005-12-01 00:00:00
abstract::Identifying the causes of high fever syndromes such as Kawasaki disease (KD) remains challenging. To investigate pathogen exposure signatures in suspected pathogen-mediated diseases such as KD, we performed immunoglobulin (Ig) profiling using a next-generation sequencing method. After intravenous Ig (IVIG) treatment, ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddy176
更新日期:2018-08-01 00:00:00
abstract::Plasmid pRSVL persisted and expressed luciferase for at least 19 months in mouse skeletal muscle after intramuscular injection. Other injected plasmids also stably expressed long-term suggesting that any plasmid DNA could stably persist and express in muscle. Plasmid DNA was demonstrated by quantitative PCR in some of...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/1.6.363
更新日期:1992-09-01 00:00:00
abstract::Expression of misfolded protein in cultured cells frequently leads to the formation of juxtanuclear inclusions that have been termed 'aggresomes'. Aggresome formation is an active cellular response that involves trafficking of the offending protein along microtubules, reorganization of intermediate filaments and recru...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddg074
更新日期:2003-04-01 00:00:00
abstract::Metabolic control of phenylalanine concentrations in body fluids is essential for cognitive development and executive function. The hepatic phenylalanine hydroxylating system is regulated by the ratio of l-phenylalanine, which is substrate of phenylalanine hydroxylase (PAH), to the PAH cofactor tetrahydrobiopterin (BH...
journal_title:Human molecular genetics
pub_type: 杂志文章
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更新日期:2018-05-15 00:00:00
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journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddh071
更新日期:2004-03-15 00:00:00