Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases.
Yun Rose LiJin LiSihai D ZhaoJonathan P BradfieldFrank D MentchS Melkorka MaggadottirCuiping HouDebra J AbramsDiana ChangFeng GaoYiran GuoZhi WeiJohn J ConnollyChristopher J CardinaleMarina BakayJoseph T GlessnerDong LiCharlly KaoKelly A ThomasHaijun QiuRosetta M ChiavacciCecilia E KimFengxiang WangJames SnyderMarylyn D RichieBerit FlatøØystein FørreLee A DensonSusan D ThompsonMara L BeckerStephen L GutheryAnna LatianoElena PerezElena ResnickRichard K RussellDavid C WilsonMark S SilverbergVito AnneseBenedicte A LieMarilynn PunaroMarla C DubinskyDimitri S MonosCaterina StrisciuglioAnnamaria StaianoErasmo MieleSubra KugathasanJustine A EllisJane E MunroKathleen E SullivanCarol A WiseHelen ChapelCharlotte Cunningham-RundlesStruan F A GrantJordan S OrangePatrick M A SleimanEdward M BehrensAnne M GriffithsJack SatsangiTerri H FinkelAlon KeinanEline T Luning PrakConstantin PolychronakosRobert N BaldassanoHongzhe LiBrendan J KeatingHakon HakonarsonPublished in: Nature medicine (2015)
Genome-wide association studies (GWASs) have identified hundreds of susceptibility genes, including shared associations across clinically distinct autoimmune diseases. We performed an inverse χ(2) meta-analysis across ten pediatric-age-of-onset autoimmune diseases (pAIDs) in a case-control study including more than 6,035 cases and 10,718 shared population-based controls. We identified 27 genome-wide significant loci associated with one or more pAIDs, mapping to in silico-replicated autoimmune-associated genes (including IL2RA) and new candidate loci with established immunoregulatory functions such as ADGRL2, TENM3, ANKRD30A, ADCY7 and CD40LG. The pAID-associated single-nucleotide polymorphisms (SNPs) were functionally enriched for deoxyribonuclease (DNase)-hypersensitivity sites, expression quantitative trait loci (eQTLs), microRNA (miRNA)-binding sites and coding variants. We also identified biologically correlated, pAID-associated candidate gene sets on the basis of immune cell expression profiling and found evidence of genetic sharing. Network and protein-interaction analyses demonstrated converging roles for the signaling pathways of type 1, 2 and 17 helper T cells (TH1, TH2 and TH17), JAK-STAT, interferon and interleukin in multiple autoimmune diseases.
Keyphrases
- genome wide
- copy number
- systematic review
- dna methylation
- genome wide association
- case control
- meta analyses
- dendritic cells
- high resolution
- poor prognosis
- signaling pathway
- rheumatoid arthritis
- gene expression
- social media
- binding protein
- drug induced
- health information
- molecular docking
- amino acid
- oxidative stress
- genome wide identification
- randomized controlled trial
- pi k akt
- ankylosing spondylitis
- protein protein
- immune response
- epithelial mesenchymal transition
- idiopathic pulmonary fibrosis
- network analysis