Abstract:
:Orienting the causal relationship between pairs of traits is a fundamental task in scientific research with significant implications in practice, such as in prioritizing molecular targets and modifiable risk factors for developing therapeutic and interventional strategies for complex diseases. A recent method, called Steiger's method, using a single SNP as an instrument variable (IV) in the framework of Mendelian randomization (MR), has since been widely applied. We report the following new contributions. First, we propose a single SNP-based alternative, overcoming a severe limitation of Steiger's method in simply assuming, instead of inferring, the existence of a causal relationship. We also clarify a condition necessary for the validity of the methods in the presence of hidden confounding. Second, to improve statistical power, we propose combining the results from multiple, and possibly correlated, SNPs as multiple instruments. Third, we develop three goodness-of-fit tests to check modeling assumptions, including those required for valid IVs. Fourth, by relaxing one of the three IV assumptions in MR, we propose several methods, including an Egger regression-like approach and its multivariable version (analogous to multivariable MR), to account for horizontal pleiotropy of the SNPs/IVs, which is often unavoidable in practice. All our methods can simultaneously infer both the existence and (if so) the direction of a causal relationship, largely expanding their applicability over that of Steiger's method. Although we focus on uni-directional causal relationships, we also briefly discuss an extension to bi-directional relationships. Through extensive simulations and an application to infer the causal directions between low density lipoprotein (LDL) cholesterol, or high density lipoprotein (HDL) cholesterol, and coronary artery disease (CAD), we demonstrate the superior performance and advantage of our proposed methods over Steiger's method and bi-directional MR. In particular, after accounting for horizontal pleiotropy, our method confirmed the well known causal direction from LDL to CAD, while other methods, including bi-directional MR, might fail.
journal_name
PLoS Genetjournal_title
PLoS geneticsauthors
Xue H,Pan Wdoi
10.1371/journal.pgen.1009105subject
Has Abstractpub_date
2020-11-02 00:00:00pages
e1009105issue
11eissn
1553-7390issn
1553-7404pii
PGENETICS-D-20-00799journal_volume
16pub_type
杂志文章相关文献
PLoS Genetics文献大全abstract::The male-specific region of the human Y chromosome (MSY) includes eight large inverted repeats (palindromes) in which arm-to-arm similarity exceeds 99.9%, due to gene conversion activity. Here, we studied one of these palindromes, P6, in order to illuminate the dynamics of the gene conversion process. We genotyped ten...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1003666
更新日期:2013-01-01 00:00:00
abstract::[This corrects the article DOI: 10.1371/journal.pgen.1006425.]. ...
journal_title:PLoS genetics
pub_type: 杂志文章,已发布勘误
doi:10.1371/journal.pgen.1006831
更新日期:2017-06-07 00:00:00
abstract::In flat-faced dog breeds, air resistance caused by skull conformation is believed to be a major determinant of Brachycephalic Obstructive Airway Syndrome (BOAS). The clinical presentation of BOAS is heterogeneous, suggesting determinants independent of skull conformation contribute to airway disease. Norwich Terriers,...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1008102
更新日期:2019-05-16 00:00:00
abstract::The Rif1 protein is a negative regulator of DNA replication initiation in eukaryotes. Here we show that budding yeast Rif1 inhibits DNA replication initiation at the rDNA locus. Absence of Rif1, or disruption of its interaction with PP1/Glc7 phosphatase, leads to more intensive rDNA replication. The effect of Rif1-Glc...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1006414
更新日期:2016-11-07 00:00:00
abstract::Practical application of genomic-based risk stratification to clinical diagnosis is appealing yet performance varies widely depending on the disease and genomic risk score (GRS) method. Celiac disease (CD), a common immune-mediated illness, is strongly genetically determined and requires specific HLA haplotypes. HLA t...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1004137
更新日期:2014-02-13 00:00:00
abstract::The evolution of insecticide resistance is a global constraint to agricultural production. Spinosad is a new, low-environmental-risk insecticide that primarily targets nicotinic acetylcholine receptors (nAChR) and is effective against a wide range of pest species. However, after only a few years of application, field ...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1000802
更新日期:2010-01-01 00:00:00
abstract::Complex traits are known to be influenced by a combination of environmental factors and rare and common genetic variants. However, detection of such multivariate associations can be compromised by low statistical power and confounding by population structure. Linear mixed effects models (LMM) can account for correlati...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1008766
更新日期:2020-05-04 00:00:00
abstract::The kinetochore is the central molecular machine that drives chromosome segregation in all eukaryotes. Genetic studies have suggested that protein sumoylation plays a role in regulating the inner kinetochore; however, the mechanism remains elusive. Here, we show that Saccharomyces cerevisiae Ulp2, an evolutionarily co...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1008477
更新日期:2019-11-20 00:00:00
abstract::Integration of genome-wide association studies (GWAS) and expression quantitative trait loci (eQTL) studies is needed to improve our understanding of the biological mechanisms underlying GWAS hits, and our ability to identify therapeutic targets. Gene-level association methods such as PrediXcan can prioritize candidat...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1007889
更新日期:2019-01-22 00:00:00
abstract::Mitochondrial translation defects can be due to mutations affecting mitochondrial- or nuclear-encoded components. The number of known nuclear genes involved in mitochondrial translation has significantly increased in the past years. RCC1L (WBSCR16), a putative GDP/GTP exchange factor, has recently been described to in...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1008923
更新日期:2020-07-31 00:00:00
abstract::Short insertions, deletions (INDELs) and larger structural variants have been increasingly employed in genetic association studies, but few improvements over SNP-based association have been reported. In order to understand why this might be the case, we analysed two publicly available datasets and observed that 63% of...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1007699
更新日期:2018-10-16 00:00:00
abstract::Understanding the extent to which ecological divergence is repeatable is essential for predicting responses of biodiversity to environmental change. Here we test the predictability of evolution, from genotype to phenotype, by studying parallel evolution in a salmonid fish, Arctic charr (Salvelinus alpinus), across ele...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1008658
更新日期:2020-04-17 00:00:00
abstract::This work analyses the genetic variation and evolutionary patterns of recessive resistance loci involved in matching-allele (MA) host-pathogen interactions, focusing on the pvr2 resistance gene to potyviruses of the wild pepper Capsicum annuum glabriusculum (chiltepin). Chiltepin grows in a variety of wild habitats in...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1006214
更新日期:2016-08-04 00:00:00
abstract::The origin and evolution of new microRNAs (miRNAs) is important because they can impact the transcriptome broadly. As miRNAs can potentially emerge constantly and rapidly, their rates of birth and evolution have been extensively debated. However, most new miRNAs identified appear not to be biologically significant. Af...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1004096
更新日期:2014-01-01 00:00:00
abstract::Introduction of DNA sequences into the genome often results in homology-dependent gene silencing in organisms as diverse as plants, fungi, flies, nematodes, and mammals. We previously showed in Cryptococcus neoformans that a repeat transgene array can induce gene silencing at a high frequency during mating (∼50%), but...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1002885
更新日期:2012-01-01 00:00:00
abstract::Under nitrogen deprivation, filaments of the cyanobacterium Anabaena undergo a process of development, resulting in a one-dimensional pattern of nitrogen-fixing heterocysts separated by about ten photosynthetic vegetative cells. Many aspects of gene expression before nitrogen deprivation and during the developmental p...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1005031
更新日期:2015-04-01 00:00:00
abstract::Nutrient stresses trigger a variety of developmental switches in the budding yeast Saccharomyces cerevisiae. One of the least understood of such responses is the development of complex colony morphology, characterized by intricate, organized, and strain-specific patterns of colony growth and architecture. The genetic ...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1000823
更新日期:2010-01-22 00:00:00
abstract::Genome-wide association studies (GWAS) have transformed our understanding of the genetics of complex traits such as autoimmune diseases, but how risk variants contribute to pathogenesis remains largely unknown. Identifying genetic variants that affect gene expression (expression quantitative trait loci, or eQTLs) is c...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1005908
更新日期:2016-03-25 00:00:00
abstract::The rate at which genomes adapt to environmental changes and the prevalence of adaptive processes in molecular evolution are two controversial issues in current evolutionary genetics. Previous attempts to quantify the genome-wide rate of adaptation through amino-acid substitution have revealed a surprising diversity o...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1005774
更新日期:2016-01-11 00:00:00
abstract::Down syndrome (DS), commonly caused by an extra copy of chromosome 21 (chr21), occurs in approximately one out of 700 live births. Precisely how an extra chr21 causes over 80 clinically defined phenotypes is not yet clear. Reduced representation bisulfite sequencing (RRBS) analysis at single base resolution revealed D...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1003515
更新日期:2013-06-01 00:00:00
abstract::[This corrects the article DOI: 10.1371/journal.pgen.1008367.]. ...
journal_title:PLoS genetics
pub_type: 已发布勘误
doi:10.1371/journal.pgen.1009131
更新日期:2020-10-08 00:00:00
abstract::Dietary restriction (DR) is the most consistent means of extending longevity in a wide range of organisms. A growing body of literature indicates that mitochondria play an important role in longevity extension by DR, but the impact of mitochondrial genotypes on the DR process have received little attention. Mitochondr...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1004354
更新日期:2014-05-15 00:00:00
abstract::Controlling infectious disease without inducing unwanted inflammatory disease requires proper regulation of the innate immune response. Thus, innate immunity needs to be activated when needed during an infection, but must be limited to prevent damage. To accomplish this, negative regulators of innate immunity limit th...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1003855
更新日期:2013-10-01 00:00:00
abstract::Undifferentiated embryonal sarcoma of the liver (UESL) is a rare and aggressive malignancy. Though the molecular underpinnings of this cancer have been largely unexplored, recurrent chromosomal breakpoints affecting a noncoding region on chr19q13, which includes the chromosome 19 microRNA cluster (C19MC), have been re...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1008642
更新日期:2020-04-20 00:00:00
abstract::Hormone-dependent activation of enhancers includes histone hyperacetylation and mediator recruitment. Histone hyperacetylation is mostly explained by a bimodal switch model, where histone deacetylases (HDACs) disassociate from chromatin, and histone acetyl transferases (HATs) are recruited. This model builds on decade...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1008770
更新日期:2020-05-26 00:00:00
abstract::The transcription factor CONSTANS (CO) is a central component that promotes Arabidopsis flowering under long-day conditions (LDs). Here, we show that the microRNA319-regulated TEOSINTE BRANCHED/CYCLOIDEA/PCF (TCP) transcription factors promote photoperiodic flowering through binding to the CO promoter and activating i...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1006833
更新日期:2017-05-30 00:00:00
abstract::Replication forks stall at different DNA obstacles such as those originated by transcription. Fork stalling can lead to DNA double-strand breaks (DSBs) that will be preferentially repaired by homologous recombination when the sister chromatid is available. The Rrm3 helicase is a replisome component that promotes repli...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1006781
更新日期:2017-05-05 00:00:00
abstract::Gap junctions are present in both vertebrates and invertebrates from nematodes to mammals. Although the importance of gap junctions has been documented in many biological processes, the molecular mechanisms underlying gap junction dynamics remain unclear. Here, using the C. elegans PLM neurons as a model, we show that...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1005948
更新日期:2016-03-25 00:00:00
abstract::Rheumatoid arthritis is a chronic inflammatory disease with a high prevalence and substantial socioeconomic burden. Despite intense research efforts, its aetiology and pathogenesis remain poorly understood. To identify novel genes and/or cellular pathways involved in the pathogenesis of the disease, we utilized a well...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.0010048
更新日期:2005-10-01 00:00:00
abstract::Innate immunity in Caenorhabditis elegans requires a conserved PMK-1 p38 mitogen-activated protein kinase (MAPK) pathway that regulates the basal and pathogen-induced expression of immune effectors. The mechanisms by which PMK-1 p38 MAPK regulates the transcriptional activation of the C. elegans immune response have n...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1000892
更新日期:2010-04-01 00:00:00