Abstract：
:We present a systematic review of pleiotropy among SNPs and genes reported to show genome-wide association with common complex diseases and traits. We find abundant evidence of pleiotropy; 233 (16.9%) genes and 77 (4.6%) SNPs show pleiotropic effects. SNP pleiotropic status was associated with gene location (p = 0.024; pleiotropic SNPs more often exonic [14.5% versus 4.9% for nonpleiotropic, trait-associated SNPs] and less often intergenic [15.8% versus 23.6%]), "predicted transcript consequence" (p = 0.001; pleiotropic SNPs more often predicted to be structurally deleterious [5% versus 0.4%] but not more often in regulatory sequences), and certain disease classes. We develop a method to calculate the likelihood that pleiotropic links between traits occurred more often than expected and demonstrate that this approach can identify etiological links that are already known (such as between fetal hemoglobin and malaria risk) and those that are not yet established (e.g., between plasma campesterol levels and gallstones risk; and between immunoglobulin A and juvenile idiopathic arthritis). Examples of pleiotropy will accumulate over time, but it is already clear that pleiotropy is a common property of genes and SNPs associated with disease traits, and this will have implications for identification of molecular targets for drug development, future genetic risk-profiling, and classification of diseases.
journal_name
Am J Hum Genetjournal_title
American journal of human geneticsauthors
Sivakumaran S,Agakov F,Theodoratou E,Prendergast JG,Zgaga L,Manolio T,Rudan I,McKeigue P,Wilson JF,Campbell Hdoi
10.1016/j.ajhg.2011.10.004subject
Has Abstractpub_date
2011-11-11 00:00:00pages
607-18issue
5eissn
0002-9297issn
1537-6605pii
S0002-9297(11)00438-1journal_volume
89pub_type
杂志文章,评审abstract：:The Hartnup mutation affects an amino acid transport system of intestine and kidney used by a large group of neutral charge alpha-amino acids (six essential and several nonessential). We compared developmental outcomes and medical histories of 21 Hartnup subjects, identified through newborn screening, with those of 19...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：
更新日期：1987-05-01 00:00:00
abstract：:Approximately 5% of patients with neurofibromatosis type 1 (NF1) exhibit gross deletions that encompass the NF1 gene and its flanking regions. The breakpoints of the common 1.4-Mb (type 1) deletions are located within low-copy repeats (NF1-REPs) and cluster within a 3.4-kb hotspot of nonallelic homologous recombinatio...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：10.1086/522089
更新日期：2007-12-01 00:00:00
abstract：:Some genes that affect development and behavior in mammals are known to be imprinted; and > or = 1% of all mammalian genes are imprinted. Hence, incorporating an imprinting parameter into linkage analysis may increase the power to detect linkage for these traits. Here we propose theoretical justifications for a recent...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：10.1086/338931
更新日期：2002-03-01 00:00:00
abstract：:The overall understanding of the molecular etiologies of intellectual disability (ID) and developmental delay (DD) is increasing as next-generation sequencing technologies identify genetic variants in individuals with such disorders. However, detailed analyses conclusively confirming these variants, as well as the und...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：10.1016/j.ajhg.2016.06.029
更新日期：2016-09-01 00:00:00
abstract：:Histochemical assay for ornithine transcarbamylase (OTC) activity in fixed frozen hepatic sections from a woman heterozygous for OTC deficiency revealed two populations of hepatocytes: those with normal activity and those with no activity. This observation, in conjunction with data from previous family studies, confir...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：
更新日期：1976-07-01 00:00:00
abstract：:To resolve uncertainty concerning the inheritance of the perinatal lethal form of osteogenesis imperfecta (OI type II), we collected family data and radiographs for 71 probands and analyzed the collagens synthesized by dermal fibroblastic cells cultured from 43 of the probands, 19 parental pairs, and single parents of...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：
更新日期：1988-02-01 00:00:00
abstract：:A patient with lactic acidosis showed a lowered pyruvate dehydrogenase E1 activity and fatigued on slight exercise. The cDNA encoding the pyruvate dehydrogenase E1 alpha-subunit from his lymphocytes, transformed by infection of Epstein-Barr virus, was cloned and sequenced. The nucleotide sequence determination reveale...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：
更新日期：1989-03-01 00:00:00
abstract：:Fibroblasts from a man with a mild form of osteogenesis imperfecta (OI) and from his son with perinatal lethal OI (OI type II) produced normal and abnormal type I procollagen molecules. The abnormal molecules synthesized by both cell strains contained one or two pro alpha 1(I) chains in which the glycine at position 5...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：
更新日期：1990-06-01 00:00:00
abstract：:We have developed a technique called "LSSP-PCR" (low-stringency single specific primer PCR) that detects single or multiple mutations in DNA. A purified DNA fragment is submitted to PCR by using a single primer specific for one of the extremities of the fragment, under conditions of very low stringency. The primer hyb...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：
更新日期：1996-03-01 00:00:00
abstract：:In recent years, many genomewide screens have been performed, to identify novel loci predisposing to various complex diseases. Often, only a portion of the collected clinical data from the study subjects is used in the actual analysis of the trait, and much of the phenotypic data is ignored. With proper consent, these...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：10.1086/321286
更新日期：2001-07-01 00:00:00
abstract：:Structural variations are among the most frequent interindividual genetic differences in the human genome. The frequency and distribution of de novo somatic structural variants in normal cells is, however, poorly explored. Using age-stratified cohorts of 318 monozygotic (MZ) twins and 296 single-born subjects, we desc...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：10.1016/j.ajhg.2011.12.009
更新日期：2012-02-10 00:00:00
abstract：:Polymorphisms of the vitamin D receptor gene (VDR) have been shown to be associated with several complex diseases, including osteoporosis, but the mechanisms are unknown and study results have been inconsistent. We therefore determined sequence variation across the major relevant parts of VDR, including construction o...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：10.1086/497438
更新日期：2005-11-01 00:00:00
abstract：:Several spin-label electron paramagnetic resonance (EPR) studies of red cell membranes appear to show abnormalities in some Huntington disease (HD) patients, but not in others. Both studies measure the W/S ratios, presumably under similar conditions, but have different results. We have studied the W/S ratio in some de...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：
更新日期：1982-05-01 00:00:00
abstract：:A mutation in transthyretin (TTR Asn 90) has been identified in the Portuguese and German populations. This variant has a lower pI and was found by screening analyses in 2/4,000 German subjects and in 4/1,200 Portuguese by using either double one-dimensional (D1-D) electrophoresis with isoelectric focusing (IEF) or hy...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：
更新日期：1991-05-01 00:00:00
abstract：:Miller-Dieker syndrome (MDS), a disorder manifesting the severe brain malformation lissencephaly ("smooth brain"), is caused, in the majority of cases, by a chromosomal microdeletion of the distal short arm of chromosome 17. Using human chromosome 17-specific DNA probes, we have begun a molecular dissection of the cri...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：
更新日期：1988-11-01 00:00:00
abstract：:Carbohydrate-deficient-glycoprotein syndrome type 1 (CDG1; also known as "Jaeken syndrome") is an autosomal recessive disorder characterized by defective glycosylation. Most patients show a deficiency of phosphomannomutase (PMM), the enzyme that converts mannose 6-phosphate to mannose 1-phosphate in the synthesis of G...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：10.1086/301763
更新日期：1998-03-01 00:00:00
abstract：:Benign infantile familial convulsions is an autosomal dominant disorder characterized by nonfebrile seizures, with the first attack occurring at age 3-12 mo. It is one of the rare forms of epilepsy that are inherited as monogenic Mendelian traits, thus providing a powerful tool for mapping genes involved in epileptic ...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：10.1086/514877
更新日期：1997-10-01 00:00:00
abstract：:Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is a serious and potentially fatal inherited defect in the beta-oxidation of fatty acids. Approximately 80% of patients with MCAD deficiency are homozygous for a single disease-causing mutation (G985). The remaining patients (except for a few cases worldwide) are c...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：
更新日期：1993-09-01 00:00:00
abstract：:Cranial neural crest (CNC) is a multipotent migratory cell population that gives rise to most of the craniofacial bones. An intricate network mediates CNC formation, epithelial-mesenchymal transition, migration along distinct paths, and differentiation. Errors in these processes lead to craniofacial abnormalities, inc...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：10.1016/j.ajhg.2011.01.003
更新日期：2011-02-11 00:00:00
abstract：:Huntington disease (HD) is a common autosomal dominant neurodegenerative disease with early adult-onset motor abnormalities and dementia. Many studies of HD show that huntingtin (CAG)n repeat-expansion length is a sensitive and specific marker for HD. However, there are a significant number of examples of HD in the ab...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：10.1086/324414
更新日期：2001-12-01 00:00:00
abstract：:Synaptophysin is an integral membrane protein of small synaptic vesicles in brain and endocrine cells. We have determined the structure and organization of the human synaptophysin gene and have established the chromosome localizations in man and mouse. Analysis of a cosmid clone containing the human synaptophysin gene...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：
更新日期：1990-09-01 00:00:00
abstract：:The data base of an ongoing population-based registry with multiple sources of ascertainment was used to estimate the present population load from genetic disease in more than 1 million consecutive live births. It was found that, before approximately age 25 years, greater than or equal to 53/1,000 live-born individual...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：
更新日期：1988-05-01 00:00:00
abstract：:We describe a new user-intense-learning experience that incorporates the teaching of clinical and research applications of human genetics in biochemistry while training first-year medical students to develop skills in computer access to the literature. Human genetics was incorporated into the biochemistry curriculum b...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：
更新日期：1989-04-01 00:00:00
abstract：:Genome-wide association studies (GWASs) have successfully identified thousands of genetic variants for many complex diseases; however, these variants explain only a small fraction of the heritability. Recently, genetic association studies that leverage external transcriptome data have received much attention and shown...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：10.1016/j.ajhg.2018.03.019
更新日期：2018-05-03 00:00:00
abstract：:Spinal muscular atrophy (SMA) is a clinically and genetically heterogeneous disease characterized by the degeneration of lower motor neurons. The most frequent form is linked to mutations in SMN1. Childhood SMA associated with progressive myoclonic epilepsy (SMA-PME) has been reported as a rare autosomal-recessive con...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：10.1016/j.ajhg.2012.05.001
更新日期：2012-07-13 00:00:00
abstract：:Neurofibromatosis 2 (NF2) is a genetic disorder characterized by the development of multiple nervous-system tumors in young adulthood. The NF2 gene has recently been isolated and found to encode a new member of the protein 4.1 family of cytoskeletal associated proteins, which we have named merlin. To define the molecu...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：
更新日期：1994-08-01 00:00:00
abstract：:This article provides evidence that selection has been a significant force during the evolution of the human mitochondrial genome. Both gene-by-gene and whole-genome approaches were used here to assess selection in the 560 mitochondrial DNA (mtDNA) coding-region sequences that were used previously for reduced-median-n...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：10.1086/381505
更新日期：2004-02-01 00:00:00
abstract：:Fibroblast cultures from 12 unrelated patients with classical Menkes disease were analyzed for mutations in the MNK gene, by reverse transcription-PCR (RT-PCR) and chemical cleavage mismatch detection. Mutations were observed in 10 patients, and in each case a different mutation was present. All of the mutations would...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：
更新日期：1994-11-01 00:00:00
abstract：:Mutations in the progressive ankylosis gene (Ank/ANKH) cause surprisingly different skeletal phenotypes in mice and humans. In mice, recessive loss-of-function mutations cause arthritis, ectopic crystal formation, and joint fusion throughout the body. In humans, some dominant mutations cause chondrocalcinosis, an adul...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：10.1086/509881
更新日期：2006-12-01 00:00:00
abstract：:Linkage is a phenomenon that correlates the genotypes of loci, rather than the phenotypes of one locus to the genotypes of another. It is therefore necessary to convert the observed trait phenotypes into trait-locus genotypes, which can then be analyzed for coinheritance with marker-locus genotypes. However, if the mo...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：10.1086/302797
更新日期：2000-03-01 00:00:00
