Region-Based Association Analysis of Human Quantitative Traits in Related Individuals

Belonogova, Nadezhda M.; Svishcheva, G. R.; Duijn, Cornelia M. van; Aulchenko, Yurii S.; Axenovich, Tatiana I.

doi:10.1371/journal.pone.0065395

Cited by 30 publications

(32 citation statements)

References 35 publications

(41 reference statements)

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“…35 The GenABEL R package was used to eliminate the effect of relatedness from the trait. Corrected environmental residuals were estimated according to the formula: trait~sex +age+genomic kinship using the GRAMMAR+ method 36 as implemented in the GenABEL 1.7-2. MixABEL 35 was used for running the linear regressions between the estimated residuals and all the imputed SNPs.…”

Section: Association Analysismentioning

confidence: 99%

Genome-wide association analysis on five isolated populations identifies variants of the HLA-DOA gene associated with white wine liking

Pirastu

Kooyman

Traglia³

et al. 2015

Eur J Hum Genet

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Wine is the most popular alcoholic beverage around the world and because of its importance in society has been widely studied. Understanding what drives its flavor has been a quest for decades but much is still unknown and will be determined at least in part by individual taste preferences. Recently studies in the genetics of taste have uncovered the role of different genes in the determination of food preferences giving new insight on its physiology. In this context we have performed a genome-wide association study on red and white wine liking using three isolated populations collected in Italy, and replicated our results on two additional populations coming from the Netherland and Central Asia for a total of 3885 samples. We have found a significant association (P = 2.1 × 10 − 8 ) between white wine liking and rs9276975:C4T a polymorphism in the HLA-DOA gene encoding a non-canonical MHC II molecule, which regulates other MHC II molecules. The same association was also found with red wine liking (P = 8.3 × 10 − 6 ). Sex-separated analysis have also revealed that the effect of HLA-DOA is twice as large in women as compared to men suggesting an interaction between this polymorphism and gender. Our results are one of the first examples of genome-wide association between liking of a commonly consumed food and gene variants. Moreover, our results suggest a role of the MHC system in the determination of food preferences opening new insight in this field in general. INTRODUCTIONWine is probably the oldest produced beverage in human history dating its first apparition in Georgia 7000 BC. It is extremely important for many cultures not only for its economy but also from the social and religious point of view. For these reasons it is also the most common and consumed type of alcoholic beverage throughout the world. 1,2 In addition, several studies indicate that modest wine consumption can have some beneficial health effects, including protection against cardiovascular and Alzheimer's disease. [3][4][5][6] There has been extensive research aiming to improve both its production and its flavor. The taste of wine depends on many different sensory perceptions ranging from taste and olfaction to texture. 7 Wine is a mixture of thousands of molecules that can contribute to its final taste, 8 and its composition varies greatly depending on the grapes used, climate and production method. 9 Although the flavor of some of these compounds is very well known, it is really difficult to understand what their role in final taste is. 7,10,11 The relevant role of genetic factors both on alcohol consumption and dependence has been clearly demonstrated by genome-wide association study (GWAS) studies. [12][13][14][15][16] Moreover, studies on the genetic variations in bitter taste receptors have also shown that variations in TAS2R16 and TAS2R38 genes can influence alcohol intake [17][18][19] but not dependence. 19 On the contrary, very little is known about the possible contribution of genetic factors to alcohol preferences in humans. Recen...

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Section: Association Analysismentioning

confidence: 99%

Genome-wide association analysis on five isolated populations identifies variants of the HLA-DOA gene associated with white wine liking

Pirastu

Kooyman

Traglia³

et al. 2015

Eur J Hum Genet

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“…The vertical and horizontal dashed lines represent the Bonferroni corrected 5% significance threshold in ordinary GWAS and 5% threshold for the exact p-values, respectively. (A) A binary (case-control) trait was simulated in each replicate, and P gwa was obtained via the procedure in GenABEL; (B) A normally distributed trait was simulated, and P gwa was obtained using the procedure in GenABEL , with GRAMMAR+ ( from ; Belonogova et al ., 2013) transformed phenotype to control for population stratification.…”

Section: Examples and Resultsmentioning

confidence: 99%

Flaw or discovery? Calculating exact p-values for genome-wide association studies in inbred populations

Shen

2015

Preprint

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Motivation: Genome-wide association studies have been conducted in inbred populations where the sample size is small. The ordinary association p-values and multiple testing correction therefore become questionable, as the detected genetic effect may or may not be due to chance, depending on the minor allele frequency distribution across the genome. Instead of permutation testing, marker-specific false positive rate can be analytically calculated in inbred populations without heterozygotes. Results: Solutions of exact p-values for genome-wide association studies in inbred populations were derived and implemented. An example is presented to illustrate that the marker-specific experiment-wise p-value varies as the genome-wide minor allele frequency distribution changes. A simulation using real Arabidopsis thaliana genome indicates that the use of exact p-values improves detection power and reduces inflation due to population structure. An analysis of a defense-related case-control phenotype using the exact p-values revealed the causal locus, where markers with higher MAFs had smaller p-values than the top variants with lower MAFs in ordinary genome-wide association analysis. Availability and Implementation: Project URL: https://r-forge.r-project.org/projects/statomics/. The R package p.exact: https://r-forge.r-project.org/R/?group_id=2030. Contact: xia.shen@ki.se

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“…Among the genes that passed this threshold, a random set of 200 traits was selected. For each of these traits, GWA were performed in two hundred permuted datasets where GRAMMAR+ transformed residuals (Belonogova, Svishcheva et al 2013, Forsberg, Andreatta et al 2015) were used as phenotype, resulting in 40,000 permutations in total. Based on this total distribution, we derived a 1% significance threshold (-log 10 (p-value) = 6.84).…”

Section: Discussionmentioning

confidence: 99%

Genetic regulation of transcriptional variation in naturalArabidopsis thalianaaccessions

Zan

Shen

Forsberg

et al. 2016

Preprint

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An increased knowledge of the genetic regulation of expression in Arabidopsis thaliana is likely to provide important insights about the basis of the plant’s extensive phenotypic variation. Here, we reanalysed two publicly available datasets with genome-wide data on genetic and transcript variation in large collections of natural A. thaliana accessions. Transcripts from more than half of all genes were detected in the leaf of all accessions, and from nearly all annotated genes in at least one accession. Thousands of genes had high transcript levels in some accessions but no transcripts at all in others and this pattern was correlated with the genome-wide genotype. In total, 2,669 eQTL were mapped in the largest population, and 717 of them were replicated in the other population. 646 cis-eQTLs regulated genes that lacked detectable transcripts in some accessions, and for 159 of these we identified one, or several, common structural variants in the populations that were shown to be likely contributors to the lack of detectable RNA-transcripts for these genes. This study thus provides new insights on the overall genetic regulation of global gene-expression diversity in the leaf of natural A. thaliana accessions. Further, it also shows that strong cis-acting polymorphisms, many of which are likely to be structural variations, make important contributions to the transcriptional variation in the worldwide A. thaliana population.

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Region-Based Association Analysis of Human Quantitative Traits in Related Individuals

Cited by 30 publications

References 35 publications

Genome-wide association analysis on five isolated populations identifies variants of the HLA-DOA gene associated with white wine liking

Genome-wide association analysis on five isolated populations identifies variants of the HLA-DOA gene associated with white wine liking

Flaw or discovery? Calculating exact p-values for genome-wide association studies in inbred populations

Genetic regulation of transcriptional variation in naturalArabidopsis thalianaaccessions

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