A Novel Test for Detecting SNP–SNP Interactions in Case-Only Trio Studies

Balliu, Brunilda; Zaitlen, Noah

doi:10.1534/genetics.115.179846

Cited by 3 publications

(2 citation statements)

References 33 publications

(54 reference statements)

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“…One limitation of this pipeline is that it cannot produce signatures that contain combinations of variants. This problem is commonly referred as SNP to SNP interaction induction (Balliu and Zaitlen, 2016). The large number of tested genotypes in a typical GWAS experiment makes prohibitive the efficient computation of variant combinations.…”

Section: Methodsmentioning

confidence: 99%

Scanning of Genetic Variants and Genetic Mapping of Phenotypic Traits in Gilthead Sea Bream Through ddRAD Sequencing

et al. 2019

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Gilthead sea bream (Sparus aurata) is a teleost of considerable economic importance in Southern European aquaculture. The aquaculture industry shows a growing interest in the application of genetic methods that can locate phenotype–genotype associations with high economic impact. Through selective breeding, the aquaculture industry can exploit this information to maximize the financial yield. Here, we present a Genome Wide Association Study (GWAS) of 112 samples belonging to seven different sea bream families collected from a Greek commercial aquaculture company. Through double digest Random Amplified DNA (ddRAD) Sequencing, we generated a per-sample genetic profile consisting of 2,258 high-quality Single Nucleotide Polymorphisms (SNPs). These profiles were tested for association with four phenotypes of major financial importance: Fat, Weight, Tag Weight, and the Length to Width ratio. We applied two methods of association analysis. The first is the typical single-SNP to phenotype test, and the second is a feature selection (FS) method through two novel algorithms that are employed for the first time in aquaculture genomics and produce groups with multiple SNPs associated to a phenotype. In total, we identified 9 single SNPs and 6 groups of SNPs associated with weight-related phenotypes (Weight and Tag Weight), 2 groups associated with Fat, and 16 groups associated with the Length to Width ratio. Six identified loci (Chr4:23265532, Chr6:12617755, Chr:8:11613979, Chr13:1098152, Chr15:3260819, and Chr22:14483563) were present in genes associated with growth in other teleosts or even mammals, such as semaphorin-3A and neurotrophin-3. These loci are strong candidates for future studies that will help us unveil the genetic mechanisms underlying growth and improve the sea bream aquaculture productivity by providing genomic anchors for selection programs.

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Section: Methodsmentioning

confidence: 99%

Scanning of Genetic Variants and Genetic Mapping of Phenotypic Traits in Gilthead Sea Bream Through ddRAD Sequencing

et al. 2019

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“…A common approach to computing the genome-wide threshold is to divide the significance level of 0.05 by the number of Linkage Disequilibrium (LD) blocks, where an LD block is a subset of consecutive SNPs which are highly correlated ( 44 ). The number of LD blocks was estimated using the R package trio ( 47 ) and was equal to 13,540, yielding a p -value threshold of (0.05/13,540) = 3.692762e-06 (which is in the range of p -value thresholds computed in several recent dog GWAS studies). The LD blocks included singleton SNPs.…”

Section: Methodsmentioning

confidence: 99%

Adrenocortical Challenge Response and Genomic Analyses in Scottish Terriers With Increased Alkaline Phosphate Activity

et al. 2018

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Scottish terriers (ST) frequently have increased serum alkaline phosphatase (ALP) of the steroid isoform. Many of these also have high serum concentrations of adrenal sex steroids. The study's objective was to determine the cause of increased sex steroids in ST with increased ALP. Adrenal gland suppression and stimulation were compared by low dose dexamethasone (LDDS), human chorionic gonadotropin (HCG) and adrenocorticotropic hormone (ACTH) response tests. Resting plasma pituitary hormones were measured. Steroidogenesis-related mRNA expression was evaluated in six ST with increased ALP, eight dogs of other breeds with pituitary-dependent hyperadrenocorticism (HAC), and seven normal dogs. The genome-wide association of single nucleotide polymorphisms (SNP) with ALP activity was evaluated in 168 ST. ALP (reference interval 8–70 U/L) was high in all ST (1,054 U/L) and HAC (985 U/L) dogs. All HAC dogs and 2/8 ST had increased cortisol post-ACTH administration. All ST and 2/7 Normal dogs had increased sex steroids post-ACTH. ST and Normal dogs had similar post-challenge adrenal steroid profiles following LDDS and HCG. Surprisingly, mRNA of hydroxysteroid 17-beta dehydrogenase 2 (HSD17B2) was lower in ST and Normal dogs than HAC. HSD17B2 facilities metabolism of sex steroids. A SNP region was identified on chromosome 5 in proximity to HSD17B2 that correlated with increased serum ALP. ST in this study with increased ALP had a normal pituitary-adrenal axis in relationship to glucocorticoids and luteinizing hormone. We speculate the identified SNP and HSD17B2 gene may have a role in the pathogenesis of elevated sex steroids and ALP in ST.

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TrioMDR: Detecting SNP interactions in trio families with model-based multifactor dimensionality reduction

Liu

Ren

et al. 2019

Genomics

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Single nucleotide polymorphism (SNP) interactions can explain the missing heritability of common complex diseases. Many interaction detection methods have been proposed in genome-wide association studies, and they can be divided into two types: population-based and family-based. Compared with population-based methods, family-based methods are robust vs. population stratification. Several family-based methods have been proposed, among which Multifactor Dimensionality Reduction (MDR)-based methods are popular and powerful. However, current MDR-based methods suffer from heavy computational burden. Furthermore, they do not allow for main effect adjustment. In this work we develop a two-stage model-based MDR approach (TrioMDR) to detect multi-locus interaction in trio families (i.e., two parents and one affected child). TrioMDR combines the MDR framework with logistic regression models to check interactions, so TrioMDR can adjust main effects. In addition, unlike consuming permutation procedures used in traditional MDR-based methods, TrioMDR utilizes a simple semi-parameter P-values correction procedure to control type I error rate, this procedure only uses a few permutations to achieve the significance of a multi-locus model and significantly speeds up TrioMDR. We performed extensive experiments on simulated data to compare the type I error and power of TrioMDR under different scenarios. The results demonstrate that TrioMDR is fast and more powerful in general than some recently proposed methods for interaction detection in trios. The R codes of TrioMDR are available at: https://github.com/TrioMDR/TrioMDR.

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A Novel Test for Detecting SNP–SNP Interactions in Case-Only Trio Studies

Cited by 3 publications

References 33 publications

Scanning of Genetic Variants and Genetic Mapping of Phenotypic Traits in Gilthead Sea Bream Through ddRAD Sequencing

Scanning of Genetic Variants and Genetic Mapping of Phenotypic Traits in Gilthead Sea Bream Through ddRAD Sequencing

Adrenocortical Challenge Response and Genomic Analyses in Scottish Terriers With Increased Alkaline Phosphate Activity

TrioMDR: Detecting SNP interactions in trio families with model-based multifactor dimensionality reduction

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