scholarly journals A genome-wide genetic pleiotropy approach identified shared loci between multiple system atrophy and inflammatory bowel disease

2019 ◽  
Author(s):  
Alexey A Shadrin ◽  
Sören Mucha ◽  
David Ellinghaus ◽  
Mary B Makarious ◽  
Cornelis Blauwendraat ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Multiple System Atrophy ◽  
Bowel Disease ◽  
Molecular Mechanisms ◽  
Gut Dysfunction ◽  
Genome Wide ◽  
A Genome ◽  
Genetic Overlap ◽  
Inflammatory Bowel ◽  
Shared Genetic

ABSTRACTWe aimed to identify shared genetic background between multiple system atrophy (MSA) and autoimmune diseases by using the conjFDR approach. Our study showed significant genetic overlap between MSA and inflammatory bowel disease and identified DENND1B, C7, and RSP04 loci, which are linked to significant changes in methylation or expression levels of adjacent genes. We obtained evidence of enriched heritability involving immune/digestive categories. Finally, an MSA mouse model showed dysregulation of the C7 gene in the degenerating midbrain compared to wildtype mice. The results identify novel molecular mechanisms and implicate immune and gut dysfunction in MSA pathophysiology.

scholarly journals A genome-wide polygenic approach to HIV acquisition uncovers link to inflammatory bowel disease and identifies potential novel genetic variants

2017 ◽  
Author(s):  
Robert A. Power ◽  
Christian W. Thorball ◽  
Istvan Bartha ◽  
John R.B. Perry ◽  
Paul J McLaren ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Risk Taking ◽  
Bowel Disease ◽  
Genome Wide ◽  
A Genome ◽  
Genetic Overlap ◽  
Inflammatory Bowel ◽  
Hiv Acquisition ◽  
Hiv 1

AbstractPolygenic approaches using genome-wide data have been hugely successful in confirming and quantifying the heritability of complex human traits. Here, we highlight their ability to identify potential novel risk variants by looking for variants with pleiotropic effect in genetically overlapping phenotypes.We used LD Score Regression in a sample of 6,315 HIV+ European individuals and 7,247 controls to test for phenotypes genetically overlapping with susceptibility to HIV-1 infection. Using LD Hub, a web tool that performs LD Score Regression, identified two phenotypes with significant genetic overlap: schizophrenia (rG =0.19, p=0.0007 and ulcerative colitis (rG=0.22, p= 0.0061). We further showed that the genetic overlap between HIV acquisition and schizophrenia is likely driven in part by their shared overlap with cannabis use and sexual behavior. BUMHBOX analyses suggested that these genetic overlaps were driven by genome-wide pleiotropy with HIV acquisition rather than heterogeneity within the HIV acquisition sample. The two diseases identified as genetically overlapping with HIV-1 acquisition have >100 associated variants, and we tested if any of them significantly associated with HIV acquisition. We observed three variants that exceeded our threshold for statistical significance. Two of these were eQTLs in whole blood for genes coding for proteins suspected to be involved in HIV biology: rs1819333 in CCR6 (p=0.0002) and rs4932178 in FURIN (p=0.00033). However, no signal was found for these variants in two smaller African samples totaling 1015 cases and 963 controls, though the mode of acquisition and genetic architecture of these populations differed.These results highlight the ability to use polygenic methods to gain new insights into complex diseases and identify potential associations with individual variants. Crucially, the leveraging of existing, publically available data makes these methods a cost-effective approach. In this case, our results add to the evidence for the role of risk taking behavior and inflammation of the bowel in HIV acquisition.Author SummaryThe biology of what puts certain individuals at greater risk of HIV acquisition is poorly understood. Using several novel polygenic methods, we identify supporting evidence for two important factors leading to acquisition. First, the role of an individual’s genetic predisposition to risk taking behaviours such as number of sexual partners, age at first sexual intercourse drug use, and mental health problems. Second, the role of gut inflammation, in particular a genetic overlap between HIV acquisition with inflammatory bowel disease and the potential role of CCR6 during infection.

A genome wide screen in an unusually large inflammatory bowel disease pedigree: Suggestive evidence for linkage on chromosomes 18p, 7p and 15q; No evidence for IBD1 or IBD2 loci

2001 ◽  
Vol 120 (5) ◽  
pp. A37
Author(s):  
Amir S. Karban ◽  
Carolien I.M. Panhuysen ◽  
Joan E. Bailey-Wilson ◽  
Yael Friedman ◽  
Geoffrey Ravenhill ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Suggestive Evidence ◽  
Genome Wide ◽  
A Genome ◽  
Inflammatory Bowel

scholarly journals Genome-wide association study reveals genetic link between diarrhea-associated Entamoeba histolytica infection and inflammatory bowel disease

2017 ◽  
Author(s):  
Genevieve L Wojcik ◽  
Chelsea Marie ◽  
Mayuresh M Abhyankar ◽  
Nobuya Yoshida ◽  
Koji Watanabe ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Association Study ◽  
Entamoeba Histolytica ◽  
Bowel Disease ◽  
Fixed Effects ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Genome Wide ◽  
A Genome ◽  
Inflammatory Bowel

AbstractDiarrhea is the second leading cause of death for children globally, causing 760,000 deaths each year in children under the age of 5. Amoebic dysentery contributes significantly to this burden, especially in developing countries. We hypothesize that genetic variation contributes to susceptibility to diarrhea-associated Entamoeba histolytica infection in Bangladeshi infants; thus, we conducted a genome-wide association study (GWAS) in two independent birth cohorts of diarrhea-associated E. histolytica infection. Cases were defined as children with at least one diarrheal episode positive for E. histolytica through either PCR or ELISA within the first year of life. Controls were children without any episodes positive for E. histolytica in the same time frame. Meta-analyses under a fixed-effects inverse variance weighting model identified variants in two neighboring genes on chromosome 10: CUL2 (cullin 2) and CREM (cAMP responsive element modulator) associated with E. histolytica infection, with SNP rs58000832 achieving genome-wide significance (Pmeta=4.2x10−10). Each additional risk allele (an intergenic insertion between CREM and CCNY) of rs58000832 conferred 2.5 increased odds of a diarrhea-associated E. histolytica infection. The most associated SNP within a gene was in an intron of CREM (rs58468685, Pmeta=2.3x10−9), which with CUL2, has been implicated as a susceptibility locus for Inflammatory Bowel Disease (IBD) and Crohn’s Disease. Gene expression resources suggest these loci are related to the higher expression of CREM, but not CUL2. Increased CREM expression is also observed in early E. histolytica infection. Further, CREM-/- mice were more susceptible to E. histolytica amebic colitis. These genetic associations reinforce the pathological similarities observed in gut inflammation between E. histolytica infection and IBD.

Stratification by CARD15 variant genotype in a genome-wide search for inflammatory bowel disease susceptibility loci

2003 ◽  
Vol 113 (6) ◽  
pp. 514-521 ◽  
Author(s):  
Sarah H. Shaw ◽  
Jochen Hampe ◽  
Ray White ◽  
Christopher G. Mathew ◽  
Mark E. Curran ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Disease Susceptibility ◽  
Susceptibility Loci ◽  
Genome Wide ◽  
A Genome ◽  
Genome Wide Search ◽  
Variant Genotype ◽  
Inflammatory Bowel
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