Genome-Wide Interaction and Pathway Association Studies for Body Mass Index

Jiao, Hongxiao; Zang, Yong; Zhang, Miaomiao; Zhang, Yuan; Wang, Yaogang; Wang, Kai; Price, Richard A.; Li, Wei Dong

doi:10.3389/fgene.2019.00404

Cited by 7 publications

(8 citation statements)

References 55 publications

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“…Across each ancestry-specific subgroup, our findings overlap with results from other work showing evidence for the importance of epistasis in human immunity, particularly involving the Major Histocompatibility Complex (MHC) [101][102][103][104][105][106][107], as well as the key roles metabolic processes and cellular signaling play in trait architecture for model systems [108][109][110][111][112][113][114]. Most notably, however, the majority of our results occurred within the African subgroup: 165 out of 245 significant pathways across all analyses.…”

Section: Multiethnic Analyses Enables the Detection Of Pathway-level supporting

confidence: 78%

Pathway Analysis within Multiple Human Ancestries Reveals Novel Signals for Epistasis in Complex Traits

Turchin

Darnell

Crawford

et al. 2020

Preprint

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Genome-wide association (GWA) studies have identified thousands of significant genetic associations in humans across a number of complex traits. However, the majority of these studies focus on linear additive relationships between genotypic and phenotypic variation. Epistasis, or non-additive genetic interactions, has been identified as a major driver of both complex trait architecture and evolution in multiple model organisms; yet, this same phenomenon is not considered to be a significant factor underlying human complex traits. There are two possible reasons for this assumption. First, most large GWA studies are conducted solely with European cohorts; therefore, our understanding of broad-sense heritability for many complex traits is limited to just one ancestry group. Second, current epistasis mapping methods commonly identify significant genetic interactions by exhaustively searching across all possible pairs of SNPs. In these frameworks, estimated epistatic effects size are often small and power can be low due to the multiple testing burden. Here, we present a case study that uses a novel region-based mapping approach to analyze sets of variants for the presence of epistatic effects across six diverse subgroups within the UK Biobank. We refer to this method as the “MArginal ePIstasis Test for Regions” or MAPIT-R. Even with limited sample sizes, we find a total of 245 pathways within the KEGG and REACTOME databases that are significantly enriched for epistatic effects in height and body mass index (BMI), with 67% of these pathways being detected within individuals of African ancestry. As a secondary analysis, we introduce a novel region-based “leave-one-out” approach to localize pathway-level epistatic signals to specific interacting genes in BMI. Overall, our results indicate that non-European ancestry populations may be better suited for the discovery of non-additive genetic variation in human complex traits — further underscoring the need for publicly available, biobank-sized datasets of diverse groups of individuals.

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Section: Multiethnic Analyses Enables the Detection Of Pathway-level supporting

confidence: 78%

Pathway Analysis within Multiple Human Ancestries Reveals Novel Signals for Epistasis in Complex Traits

Turchin

Darnell

Crawford

et al. 2020

Preprint

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“…In the pathway-based association analysis, the Tob1 pathway, which contributes to obesity through the mitogen-activated protein kinase (MAPK) pathway, showed the most significant association with BMI. These findings were also replicated in different human populations [ 22 ]. In addition, we analyzed the general linkage disequilibrium (LD) within +/−100 Kb around the EXOC4 gene via Haploview.…”

Section: Introductionmentioning

confidence: 57%

“…EXOC4 is also involved in insulin, triiodothyronine, and thyroxine secretion in Chinese Holstein cattle [ 27 ]. Jiao et al investigated the interactions between EXOC4 -1q23.1 and BMI in a European–American adult female cohort via genome-wide interaction analyses, and results suggest that EXOC4 -related pathways may contribute to the development of obesity [ 22 ]. Similarly, after EXOC4 knockout in embryos, mice can form gastrointestinal embryos normally, but are unable to progress beyond the primitive streak stage and die shortly after [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

“…We analyzed the general linkage disequilibrium (LD) within +/−100 Kb of the EXOC4 gene via Haploview, and the location diagram of the SNP, exons, deletion, binding sites, and promoter is shown in Figure 1 . Then, the potential transcription factor binding region was also predicted by TFBIND [ 21 ] and Jaspar [ 22 ]. The results of the potential transcription factor binding site were scored by TFBIND.…”

Section: Methodsmentioning

confidence: 99%

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The Association of an SNP in the EXOC4 Gene and Reproductive Traits Suggests Its Use as a Breeding Marker in Pigs

Zhou

Zheng

et al. 2021

Animals

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In mammals, the exocyst complex component 4 (EXOC4) gene has often been reported to be involved in vesicle transport. The SNP rs81471943 (C/T) is located in the intron of porcine EXOC4, while six quantitative trait loci (QTL) within 5–10 Mb around EXOC4 are associated with ovary weight, teat number, total offspring born alive, and corpus luteum number. However, the molecular mechanisms between EXOC4 and the reproductive performance of pigs remains to be elucidated. In this study, rs81471943 was genotyped from a total of 994 Duroc sows, and the genotype and allele frequency of SNP rs81471943 (C/T) were statistically analyzed. Then, the associations between SNP rs81471943 and four reproductive traits, including number of piglets born alive (NBA), litter weight at birth (LWB), number of piglets weaned (NW), and litter weight at weaning (LWW), were determined. Sanger sequencing and PCR restriction fragment length polymorphism (PCR-RFLP) were utilized to identify the rs81471943 genotype. We found that the genotype frequency of CC was significantly higher than that of CT and TT, and CC was the most frequent genotype for NBA, LWB, NW, and LWW. Moreover, 5′-deletion and luciferase assays identified a positive transcription regulatory element in the EXOC4 promoter. After exploring the EXOC4 promoter, SNP -1781G/A linked with SNP rs81471943 (C/T) were identified by analysis of the transcription activity of the haplotypes, and SNP -1781 G/A may influence the potential binding of P53, E26 transformation specific sequence -like 1 transcription factor (ELK1), and myeloid zinc finger 1 (MZF1). These findings provide useful information for identifying a molecular marker of EXOC4-assisted selection in pig breeding.

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“…One study indicates that the mutation of specific SNPs loci in EXOC4 leads to an increase in the malformation rate of human newborns [21], and EXOC4 also involves in insulin-stimulated glucose transport [22,23]. Jiao et al investigated the interactions between EXOC4-1q23.1 and body mass index in a European-American adult female cohort via genome-wide interaction analyses, and results suggest EXOC4-related pathways may contribute to the development of obesity [24]. Similarly, after EXOC4 knockout in embryos, mice can form gastrointestinal embryos normally, but are unable to progress beyond the primitive streak stage and die shortly [25].…”

Section: Discussionmentioning

confidence: 99%

Association of rs81471943 and reproductive traits reveals EXOC4 as novel molecular breeding marker in pigs

Zhou

et al. 2020

Preprint

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Background: In mammals, the exocyst complex component 4 ( EXOC 4 ) gene has often been reported to be involved in vesicle transport. The rs81471943 (C/T) locates at the intron of porcine EXOC 4 , and six quantitative trait loci (QTLs) within 5-10 Mb around EXOC 4 are associated with ovary weight, teat number, total born alive, and corpus luteum number. However, the molecular mechanisms between EXOC 4 and reproductive performance of pigs remains incompletely elucidated.Results: In this study, rs81471943 was genotyped from a total of 994 Duroc sows, and the genotype and allele frequency of rs81471943 (C/T) were statistically analyzed. Then the associations between rs81471943 and four reproductive traits including number of piglets born alive (NBA), litter weight at birth (LWB)，number of piglets weaned (NW), and litter weight at weaning (LWW) were determined. Besides, the sanger sequencing and PCR-restriction fragment length polymorphism (PCR-RFLP) were utilized to identify genotype of rs81471943. We found that the genotype frequency of CC was significantly higher than that of CT and TT, and TT was the favorable genotype on NW ( P =0.01) and LWW ( P <0.01). Moreover, 5’-deletion and luciferase assays identified a positive transcription regulatory element in -1826/-1551 of EXOC 4 . After exploring -1826/-1551 fragment, -1781G/A linked with rs81471943 (C/T) were identified by analysis the transcription activity of the haplotypes, and -1781 G/A might influence the potential binding of P 53 , ETS transcription factor ( ELK1 ), and myeloid zinc finger 1 ( MZF 1 ).Conclusions: In 994 Duroc pigs, rs81471943 of TT was the favorable genotype on NW (P=0.01) and LWW (P<0.01), and the haplotypes of -1781G/A and rs81471943 significantly affect the transcription activity of EXOC 4 , which might influence the binding of potential cis-acting elements P 53 , ELK 1 and/or MZF 1 . These findings provide useful information for identifying the molecular marker of EXOC 4 -assisted selection in pig breeding.

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Genome-Wide Interaction and Pathway Association Studies for Body Mass Index

Cited by 7 publications

References 55 publications

Pathway Analysis within Multiple Human Ancestries Reveals Novel Signals for Epistasis in Complex Traits

Pathway Analysis within Multiple Human Ancestries Reveals Novel Signals for Epistasis in Complex Traits

The Association of an SNP in the EXOC4 Gene and Reproductive Traits Suggests Its Use as a Breeding Marker in Pigs

Association of rs81471943 and reproductive traits reveals EXOC4 as novel molecular breeding marker in pigs

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