From genome-wide associations to candidate causal variants by statistical fine-mapping

Schaid, Daniel J.; Chen, Wenan; Larson, Nicholas B.

doi:10.1038/s41576-018-0016-z

Cited by 693 publications

(656 citation statements)

References 121 publications

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“…Based on these data, we can speculate that rs17064 affects ABCB1 expression, which may lead to altered vitamin D transport and status. As SNPs on the microarrays are TagSNPs (i.e., they are highly correlated to neighboring SNPs and therefore, represent many unmeasured SNPs located in the same genomic region), it cannot be excluded that rs17064 is in linkage disequilibrium with the unidentified causal variant (37). However, together with the observation that 2 SNPs in ABCB1 were previously associated with D 3 bioavailability in the same group of subjects (23), this result highly suggests that ABCB1 is involved in vitamin D homeostasis in humans by affecting both the net absorption of dietary vitamin D and the net efflux of circulating vitamin D. As gender differences in clearance have been reported for ABCB1 (38) and as estrogens can influence ABCB1 activity (39), the specific effect of ABCB1 on vitamin D status in women remains to be evaluated.…”

Section: Discussionmentioning

confidence: 99%

ABCB1 (P‐glycoprotein) regulates vitamin D absorption and contributes to its transintestinal efflux

et al. 2018

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Efficient intestinal absorption of dietary vitamin D is required in most people to ensure an adequate status. Thus, we investigated the involvement of ATP binding cassette subfamily B member 1 (ABCB1) in vitamin D intestinal efflux. Both cholecalciferol (D) and 25-hydroxycholecalciferol [25(OH)D] apical effluxes were decreased by chemical inhibition of ABCB1 in Caco-2 cells and increased by ABCB1 overexpression in Griptites or Madin-Darby canine kidney type II cells. Mice deficient for the 2 murine ABCB1s encoded by Abcb1a and Abcb1b genes ( Abcb1) displayed an accumulation of 25(OH)D in plasma, intestine, brain, liver, and kidneys, together with an increased D postprandial response after gavage compared with controls. 25(OH)D efflux through Abcb1 intestinal explants was markedly decreased compared with controls. This reduction of 25(OH)D transfer from plasma to lumen was further confirmed in vivo in intestine-perfused mice. Docking experiments established that both D and 25(OH)D could bind with high affinity to Caenorhabditis elegans P-glycoprotein, used as an ABCB1 model. Finally, in a group of 39 healthy male adults, a single-nucleotide polymorphism (SNP) in ABCB1 (rs17064) was significantly associated with the fasting plasma 25(OH)D concentration. Thus, we showed here for the first time that ABCB1 is involved in neo-absorbed vitamin D efflux by the enterocytes and that it also contributes to vitamin D transintestinal excretion and likely impacts vitamin D status.-Margier, M., Collet, X., le May, C., Desmarchelier, C., André, F., Lebrun, C., Defoort, C., Bluteau, A., Borel, P., Lespine, A., Reboul, E. ABCB1 (P-glycoprotein) regulates vitamin D absorption and contributes to its transintestinal efflux.

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Section: Discussionmentioning

confidence: 99%

ABCB1 (P‐glycoprotein) regulates vitamin D absorption and contributes to its transintestinal efflux

et al. 2018

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“…GWAS based on the Anderson−Darling (A−D) test is a complement to MLM‐based GWAS methods, especially for complex quantitative traits determined by moderate effect loci or rare variants, and with abnormal phenotype distribution (Yang et al ., ). To refine the genomic localization of causal variants identified in GWAS, fine‐mapping strategies have been developed by using statistical methods (Schaid et al ., ).…”

Section: The Development Of Gwasmentioning

confidence: 97%

Metabolic GWAS‐based dissection of genetic bases underlying the diversity of plant metabolism

2018

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Plants have served as sources providing humans with metabolites for food and nutrition, biomaterials for living, and treatment for pain and disease. Plants produce a huge array of metabolites, with an immense diversity at both the population and individual levels. Dissection of the genetic bases for metabolic diversity has attracted increasing research attention. The concept of genome-wide association study (GWAS) was extended to studies on the diversity of plant metabolome that benefitted from the development of mass-spectrometry-based analytical systems and genome sequencing technologies. Metabolic genome-wide association study (mGWAS) is one of the most powerful tools for global identification of genetic determinants for diversity of plant metabolism. Recently, mGWAS has been performed for various species with continuous improvements, providing deeper insights into the genetic bases of metabolic diversity. In this review, we discuss fully the achievements to date and remaining challenges that are associated with both mGWAS and mGWAS-based multi-dimensional analysis. We begin with a summary of GWAS and its development based on statistical methods and populations. As variation in targeted traits is essential for GWAS, we review metabolic diversity and its rise at both the population and individual levels. Subsequently, the application of mGWAS for plants and its corresponding achievements are fully discussed. We address the current knowledge on mGWAS-based multi-dimensional analysis and emerging insights into the diversity of metabolism.

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“…These mechanisms can be informed by genome-wide experiments that provide data on variations in molecular and cellular states in genotyped individuals. Most examples of such data, though, are largely observational, due in part to constraints of specific populations (e.g., humans), the limitations of existing experimental technologies, and the challenge of coordinating large numbers of experiments with multiple levels of data [2]. One approach to shed light on these dynamics is to pair complementary datasets from the same individuals and perform statistical mediation analysis (e.g., [3][4][5]), which has increasingly been used in genomics [6].…”

Section: Introductionmentioning

confidence: 99%

Integrative QTL analysis of gene expression and chromatin accessibility identifies multi-tissue patterns of genetic regulation

et al. 2020

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Gene transcription profiles across tissues are largely defined by the activity of regulatory elements, most of which correspond to regions of accessible chromatin. Regulatory element activity is in turn modulated by genetic variation, resulting in variable transcription rates across individuals. The interplay of these factors, however, is poorly understood. Here we characterize expression and chromatin state dynamics across three tissues-liver, lung, and kidney-in 47 strains of the Collaborative Cross (CC) mouse population, examining the regulation of these dynamics by expression quantitative trait loci (eQTL) and chromatin QTL (cQTL). QTL whose allelic effects were consistent across tissues were detected for 1,101 genes and 133 chromatin regions. Also detected were eQTL and cQTL whose allelic effects differed across tissues, including local-eQTL for Pik3c2g detected in all three tissues but with distinct allelic effects. Leveraging overlapping measurements of gene expression and chromatin accessibility on the same mice from multiple tissues, we used mediation analysis to identify chromatin and gene expression intermediates of eQTL effects. Based on QTL and mediation analyses over multiple tissues, we propose a causal model for the distal genetic regulation of Akr1e1, a gene involved in glycogen metabolism, through the zinc finger transcription factor Zfp985 and chromatin intermediates. This analysis demonstrates the complexity of transcriptional and chromatin dynamics and their regulation over multiple tissues, as well as the value of the CC and related genetic resource populations for identifying specific regulatory mechanisms within cells and tissues.

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From genome-wide associations to candidate causal variants by statistical fine-mapping

Cited by 693 publications

References 121 publications

ABCB1 (P‐glycoprotein) regulates vitamin D absorption and contributes to its transintestinal efflux

ABCB1 (P‐glycoprotein) regulates vitamin D absorption and contributes to its transintestinal efflux

Metabolic GWAS‐based dissection of genetic bases underlying the diversity of plant metabolism

Integrative QTL analysis of gene expression and chromatin accessibility identifies multi-tissue patterns of genetic regulation

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