Limits...
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

Functional gene network for novel pleiotropic loci from the present analysis and previously confirmed blood lipid loci.The protein-coding genes closest to the most associated SNP in the pleiotropic loci and the previously confirmed blood lipid loci were used to construct a functional similarity network of genes (see Methods). The network contains 158 gene nodes that are connected by 509 similarity edges. Genes previously reported to associate with blood lipids are represented by turquoise nodes (or turquoise node sectors). Red nodes (or red node sectors) represent pleiotropic loci between immune mediated diseases and Triglycerides (TG). Green nodes (or green node sectors) represent pleiotropic loci between immune-mediated diseases and low density lipoproteins (LDL) cholesterol. Purple nodes (or purple node sectors) represent pleiotropic loci between immune-mediated diseases and high density lipoproteins (HDL) cholesterol. Solid grey and orange edge lines indicate strong functional similarity between the connected genes based on their Gene Ontology annotations. Orange edge lines correspond to the 212 novel connections between nodes in the pleiotropic loci network and blood lipid loci network. Diamond node shapes represent the 23 new genes that arise after combining the pleiotropic loci and blood lipid loci into one network. Enriched KEGG pathways (see Tables O-P in S1 File) are connected to respective gene nodes with dotted pink lines. Genes and their nodes that are not connected to any other node in the network (48 genes) or annotated (82 genes) are omitted from the figure.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4390360&req=5

pone.0123057.g004: Functional gene network for novel pleiotropic loci from the present analysis and previously confirmed blood lipid loci.The protein-coding genes closest to the most associated SNP in the pleiotropic loci and the previously confirmed blood lipid loci were used to construct a functional similarity network of genes (see Methods). The network contains 158 gene nodes that are connected by 509 similarity edges. Genes previously reported to associate with blood lipids are represented by turquoise nodes (or turquoise node sectors). Red nodes (or red node sectors) represent pleiotropic loci between immune mediated diseases and Triglycerides (TG). Green nodes (or green node sectors) represent pleiotropic loci between immune-mediated diseases and low density lipoproteins (LDL) cholesterol. Purple nodes (or purple node sectors) represent pleiotropic loci between immune-mediated diseases and high density lipoproteins (HDL) cholesterol. Solid grey and orange edge lines indicate strong functional similarity between the connected genes based on their Gene Ontology annotations. Orange edge lines correspond to the 212 novel connections between nodes in the pleiotropic loci network and blood lipid loci network. Diamond node shapes represent the 23 new genes that arise after combining the pleiotropic loci and blood lipid loci into one network. Enriched KEGG pathways (see Tables O-P in S1 File) are connected to respective gene nodes with dotted pink lines. Genes and their nodes that are not connected to any other node in the network (48 genes) or annotated (82 genes) are omitted from the figure.

Mentions: The biological relationships between pleiotropic loci identified with the new methodology were compared with that of loci previously shown to be associated with blood lipids using standard approaches[14], applying functional gene networks and protein interaction networks as well as biological pathway enrichment analysis. Notably, the connectivity among the loci in the combined network increased considerably compared to the networks represented by pleiotropic loci and by blood lipid loci only (Fig 4). This demonstrates biological relatedness between pleiotropic loci from the present analysis and blood lipid loci from previous reports[14]. In case of the functional gene network, a 40% increase in the number of network nodes representing blood lipid loci was observed compared to previous results (Fig 4). Furthermore, as revealed by the protein interaction network, the loci representing known hypercholesterolemic mouse models (e.g. APOE [MIM 107741] and LDLR [MIM 606945]) showed only a limited functional overlap with the pleiotropic loci (Figure O in S1 File). Enriched KEGG pathways represented by the pleiotropic loci include biological functions related to glycosphingolipid synthesis (e.g. FUT2 [MIM 182100]) and to intestinal host-microbe interactions (e.g. ATG16L1 [MIM 610767]) (Figure O in S1 File). Multiple enriched pathways for the pleiotropic loci also associate with cancer development (Figure O 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)

Functional gene network for novel pleiotropic loci from the present analysis and previously confirmed blood lipid loci.The protein-coding genes closest to the most associated SNP in the pleiotropic loci and the previously confirmed blood lipid loci were used to construct a functional similarity network of genes (see Methods). The network contains 158 gene nodes that are connected by 509 similarity edges. Genes previously reported to associate with blood lipids are represented by turquoise nodes (or turquoise node sectors). Red nodes (or red node sectors) represent pleiotropic loci between immune mediated diseases and Triglycerides (TG). Green nodes (or green node sectors) represent pleiotropic loci between immune-mediated diseases and low density lipoproteins (LDL) cholesterol. Purple nodes (or purple node sectors) represent pleiotropic loci between immune-mediated diseases and high density lipoproteins (HDL) cholesterol. Solid grey and orange edge lines indicate strong functional similarity between the connected genes based on their Gene Ontology annotations. Orange edge lines correspond to the 212 novel connections between nodes in the pleiotropic loci network and blood lipid loci network. Diamond node shapes represent the 23 new genes that arise after combining the pleiotropic loci and blood lipid loci into one network. Enriched KEGG pathways (see Tables O-P in S1 File) are connected to respective gene nodes with dotted pink lines. Genes and their nodes that are not connected to any other node in the network (48 genes) or annotated (82 genes) are omitted from the figure.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0123057.g004: Functional gene network for novel pleiotropic loci from the present analysis and previously confirmed blood lipid loci.The protein-coding genes closest to the most associated SNP in the pleiotropic loci and the previously confirmed blood lipid loci were used to construct a functional similarity network of genes (see Methods). The network contains 158 gene nodes that are connected by 509 similarity edges. Genes previously reported to associate with blood lipids are represented by turquoise nodes (or turquoise node sectors). Red nodes (or red node sectors) represent pleiotropic loci between immune mediated diseases and Triglycerides (TG). Green nodes (or green node sectors) represent pleiotropic loci between immune-mediated diseases and low density lipoproteins (LDL) cholesterol. Purple nodes (or purple node sectors) represent pleiotropic loci between immune-mediated diseases and high density lipoproteins (HDL) cholesterol. Solid grey and orange edge lines indicate strong functional similarity between the connected genes based on their Gene Ontology annotations. Orange edge lines correspond to the 212 novel connections between nodes in the pleiotropic loci network and blood lipid loci network. Diamond node shapes represent the 23 new genes that arise after combining the pleiotropic loci and blood lipid loci into one network. Enriched KEGG pathways (see Tables O-P in S1 File) are connected to respective gene nodes with dotted pink lines. Genes and their nodes that are not connected to any other node in the network (48 genes) or annotated (82 genes) are omitted from the figure.
Mentions: The biological relationships between pleiotropic loci identified with the new methodology were compared with that of loci previously shown to be associated with blood lipids using standard approaches[14], applying functional gene networks and protein interaction networks as well as biological pathway enrichment analysis. Notably, the connectivity among the loci in the combined network increased considerably compared to the networks represented by pleiotropic loci and by blood lipid loci only (Fig 4). This demonstrates biological relatedness between pleiotropic loci from the present analysis and blood lipid loci from previous reports[14]. In case of the functional gene network, a 40% increase in the number of network nodes representing blood lipid loci was observed compared to previous results (Fig 4). Furthermore, as revealed by the protein interaction network, the loci representing known hypercholesterolemic mouse models (e.g. APOE [MIM 107741] and LDLR [MIM 606945]) showed only a limited functional overlap with the pleiotropic loci (Figure O in S1 File). Enriched KEGG pathways represented by the pleiotropic loci include biological functions related to glycosphingolipid synthesis (e.g. FUT2 [MIM 182100]) and to intestinal host-microbe interactions (e.g. ATG16L1 [MIM 610767]) (Figure O in S1 File). Multiple enriched pathways for the pleiotropic loci also associate with cancer development (Figure O 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