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Abundant genetic overlap between blood lipids and immune-mediated diseases indicates shared molecular genetic mechanisms.

Andreassen OA, Desikan RS, Wang Y, Thompson WK, Schork AJ, Zuber V, Doncheva NT, Ellinghaus E, Albrecht M, Mattingsdal M, Franke A, Lie BA, Mills IG, Mills I, Aukrust P, McEvoy LK, Djurovic S, Karlsen TH, Dale AM - PLoS ONE (2015)

Bottom Line: The new pleiotropic loci increased the number of functional gene network nodes representing blood lipid loci by 40%.Pathway analyses implicated several novel shared mechanisms for immune pathogenesis and lipid biology, including glycosphingolipid synthesis (e.g. FUT2) and intestinal host-microbe interactions (e.g. ATG16L1).We demonstrate a shared genetic basis for blood lipids and immune-mediated diseases independent of environmental factors.

View Article: PubMed Central - PubMed

Affiliation: NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, 0407 Oslo, Norway; Department of Psychiatry, University of California San Diego, La Jolla, CA 92093, United States of America.

ABSTRACT
Epidemiological studies suggest a relationship between blood lipids and immune-mediated diseases, but the nature of these associations is not well understood. We used genome-wide association studies (GWAS) to investigate shared single nucleotide polymorphisms (SNPs) between blood lipids and immune-mediated diseases. We analyzed data from GWAS (n~200,000 individuals), applying new False Discovery Rate (FDR) methods, to investigate genetic overlap between blood lipid levels [triglycerides (TG), low density lipoproteins (LDL), high density lipoproteins (HDL)] and a selection of archetypal immune-mediated diseases (Crohn's disease, ulcerative colitis, rheumatoid arthritis, type 1 diabetes, celiac disease, psoriasis and sarcoidosis). We found significant polygenic pleiotropy between the blood lipids and all the investigated immune-mediated diseases. We discovered several shared risk loci between the immune-mediated diseases and TG (n = 88), LDL (n = 87) and HDL (n = 52). Three-way analyses differentiated the pattern of pleiotropy among the immune-mediated diseases. The new pleiotropic loci increased the number of functional gene network nodes representing blood lipid loci by 40%. Pathway analyses implicated several novel shared mechanisms for immune pathogenesis and lipid biology, including glycosphingolipid synthesis (e.g. FUT2) and intestinal host-microbe interactions (e.g. ATG16L1). We demonstrate a shared genetic basis for blood lipids and immune-mediated diseases independent of environmental factors. Our findings provide novel mechanistic insights into dyslipidemia and immune-mediated diseases and may have implications for therapeutic trials involving lipid-lowering and anti-inflammatory agents.

No MeSH data available.


Related in: MedlinePlus

‘Conjunctional FDR Manhattan plot’ of conjunctional (FDR<0.05) values for low density lipoprotein.Conjunctional—log10(FDR) values for low density lipoproteins (LDL) cholesterol and Crohn’s Disease (CD), ulcerative colitis (UC), rheumatoid arthritis (RA), type 1 diabetes (T1D), celiac disease (CeD), psoriasis (PSOR) and G) sarcoidosis (SARC) were plotted along their chromosome locations. SNPs with conjunctional FDR < 0.05 (i.e.,—log10 FDR > 1.3) are shown with enlarged data points. A black circle around the enlarged data points indicates the most significant SNP in each LD block and this SNP was annotated with the closest gene which is listed above the symbols in each locus, except for the Major Histocompatibility Complex (MHC) region on chromosome 6. The figure shows the localization of 87 LDL loci. Details for the associated loci outside of chromosome 6 are shown in Table F in S1 File.
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pone.0123057.g002: ‘Conjunctional FDR Manhattan plot’ of conjunctional (FDR<0.05) values for low density lipoprotein.Conjunctional—log10(FDR) values for low density lipoproteins (LDL) cholesterol and Crohn’s Disease (CD), ulcerative colitis (UC), rheumatoid arthritis (RA), type 1 diabetes (T1D), celiac disease (CeD), psoriasis (PSOR) and G) sarcoidosis (SARC) were plotted along their chromosome locations. SNPs with conjunctional FDR < 0.05 (i.e.,—log10 FDR > 1.3) are shown with enlarged data points. A black circle around the enlarged data points indicates the most significant SNP in each LD block and this SNP was annotated with the closest gene which is listed above the symbols in each locus, except for the Major Histocompatibility Complex (MHC) region on chromosome 6. The figure shows the localization of 87 LDL loci. Details for the associated loci outside of chromosome 6 are shown in Table F in S1 File.

Mentions: To visualize the localization of the pleiotropic genetic variants associated with both blood lipids and immune-mediated diseases, we used a ‘Conjunction FDR Manhattan plot’, showing all SNPs with a significant conjunction FDR within an LD block in relation to their chromosomal location. As illustrated in Figs 1, 2 and 3, the enlarged data points represent the significant SNPs (FDR trait1& trait2 < 0.05), whereas the small points represent the non-significant SNPs. All SNPs without pruning are shown, and the strongest signal in each LD block is encircled in black. The strongest signal was identified after ranking all SNPs based on the conjunction FDR and removed SNPs in LD r2 > 0.2 with any higher ranked SNP (Figs 1, 2 and 3 and Figures U-W in S1 File).


Abundant genetic overlap between blood lipids and immune-mediated diseases indicates shared molecular genetic mechanisms.

Andreassen OA, Desikan RS, Wang Y, Thompson WK, Schork AJ, Zuber V, Doncheva NT, Ellinghaus E, Albrecht M, Mattingsdal M, Franke A, Lie BA, Mills IG, Mills I, Aukrust P, McEvoy LK, Djurovic S, Karlsen TH, Dale AM - PLoS ONE (2015)

‘Conjunctional FDR Manhattan plot’ of conjunctional (FDR<0.05) values for low density lipoprotein.Conjunctional—log10(FDR) values for low density lipoproteins (LDL) cholesterol and Crohn’s Disease (CD), ulcerative colitis (UC), rheumatoid arthritis (RA), type 1 diabetes (T1D), celiac disease (CeD), psoriasis (PSOR) and G) sarcoidosis (SARC) were plotted along their chromosome locations. SNPs with conjunctional FDR < 0.05 (i.e.,—log10 FDR > 1.3) are shown with enlarged data points. A black circle around the enlarged data points indicates the most significant SNP in each LD block and this SNP was annotated with the closest gene which is listed above the symbols in each locus, except for the Major Histocompatibility Complex (MHC) region on chromosome 6. The figure shows the localization of 87 LDL loci. Details for the associated loci outside of chromosome 6 are shown in Table F in S1 File.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4390360&req=5

pone.0123057.g002: ‘Conjunctional FDR Manhattan plot’ of conjunctional (FDR<0.05) values for low density lipoprotein.Conjunctional—log10(FDR) values for low density lipoproteins (LDL) cholesterol and Crohn’s Disease (CD), ulcerative colitis (UC), rheumatoid arthritis (RA), type 1 diabetes (T1D), celiac disease (CeD), psoriasis (PSOR) and G) sarcoidosis (SARC) were plotted along their chromosome locations. SNPs with conjunctional FDR < 0.05 (i.e.,—log10 FDR > 1.3) are shown with enlarged data points. A black circle around the enlarged data points indicates the most significant SNP in each LD block and this SNP was annotated with the closest gene which is listed above the symbols in each locus, except for the Major Histocompatibility Complex (MHC) region on chromosome 6. The figure shows the localization of 87 LDL loci. Details for the associated loci outside of chromosome 6 are shown in Table F in S1 File.
Mentions: To visualize the localization of the pleiotropic genetic variants associated with both blood lipids and immune-mediated diseases, we used a ‘Conjunction FDR Manhattan plot’, showing all SNPs with a significant conjunction FDR within an LD block in relation to their chromosomal location. As illustrated in Figs 1, 2 and 3, the enlarged data points represent the significant SNPs (FDR trait1& trait2 < 0.05), whereas the small points represent the non-significant SNPs. All SNPs without pruning are shown, and the strongest signal in each LD block is encircled in black. The strongest signal was identified after ranking all SNPs based on the conjunction FDR and removed SNPs in LD r2 > 0.2 with any higher ranked SNP (Figs 1, 2 and 3 and Figures U-W in S1 File).

Bottom Line: The new pleiotropic loci increased the number of functional gene network nodes representing blood lipid loci by 40%.Pathway analyses implicated several novel shared mechanisms for immune pathogenesis and lipid biology, including glycosphingolipid synthesis (e.g. FUT2) and intestinal host-microbe interactions (e.g. ATG16L1).We demonstrate a shared genetic basis for blood lipids and immune-mediated diseases independent of environmental factors.

View Article: PubMed Central - PubMed

Affiliation: NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, 0407 Oslo, Norway; Department of Psychiatry, University of California San Diego, La Jolla, CA 92093, United States of America.

ABSTRACT
Epidemiological studies suggest a relationship between blood lipids and immune-mediated diseases, but the nature of these associations is not well understood. We used genome-wide association studies (GWAS) to investigate shared single nucleotide polymorphisms (SNPs) between blood lipids and immune-mediated diseases. We analyzed data from GWAS (n~200,000 individuals), applying new False Discovery Rate (FDR) methods, to investigate genetic overlap between blood lipid levels [triglycerides (TG), low density lipoproteins (LDL), high density lipoproteins (HDL)] and a selection of archetypal immune-mediated diseases (Crohn's disease, ulcerative colitis, rheumatoid arthritis, type 1 diabetes, celiac disease, psoriasis and sarcoidosis). We found significant polygenic pleiotropy between the blood lipids and all the investigated immune-mediated diseases. We discovered several shared risk loci between the immune-mediated diseases and TG (n = 88), LDL (n = 87) and HDL (n = 52). Three-way analyses differentiated the pattern of pleiotropy among the immune-mediated diseases. The new pleiotropic loci increased the number of functional gene network nodes representing blood lipid loci by 40%. Pathway analyses implicated several novel shared mechanisms for immune pathogenesis and lipid biology, including glycosphingolipid synthesis (e.g. FUT2) and intestinal host-microbe interactions (e.g. ATG16L1). We demonstrate a shared genetic basis for blood lipids and immune-mediated diseases independent of environmental factors. Our findings provide novel mechanistic insights into dyslipidemia and immune-mediated diseases and may have implications for therapeutic trials involving lipid-lowering and anti-inflammatory agents.

No MeSH data available.


Related in: MedlinePlus