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Inflammatory bowel disease, including Crohn's disease (CD) and ulcerative colitis (UC), and type 1 diabetes (T1D) are autoimmune diseases that may share common susceptibility pathways. We examined known susceptibility loci for these diseases in a cohort of 1689 CD cases, 777 UC cases, 989 T1D cases and 6197 shared control subjects of European ancestry, who were genotyped by the Illumina HumanHap550 SNP arrays. We identified multiple previously unreported or unconfirmed disease associations, including known CD loci (ICOSLG and TNFSF15) and T1D loci (TNFAIP3) that confer UC risk, known UC loci (HERC2 and IL26) that confer T1D risk and known UC loci (IL10 and CCNY) that confer CD risk. Additionally, we show that T1D risk alleles residing at the PTPN22, IL27, IL18RAP and IL10 loci protect against CD. Furthermore, the strongest risk alleles for T1D within the major histocompatibility complex (MHC) confer strong protection against CD and UC; however, given the multi-allelic nature of the MHC haplotypes, sequencing of the MHC locus will be required to interpret this observation. These results extend our current knowledge on genetic variants that predispose to autoimmunity, and suggest that many loci involved in autoimmunity may be under a balancing selection due to antagonistic pleiotropic effect. Our analysis implies that variants with opposite effects on different diseases may facilitate the maintenance of common susceptibility alleles in human populations, making autoimmune diseases especially amenable to genetic dissection by genome-wide association studies.

A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown. We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation scores. We included 35 668 children from 20 studies in the discovery phase and 11 873 children from 13 studies in the replication phase. In total, 15 loci reached genome-wide significance (P-value < 5 × 10−8) in the joint discovery and replication analysis, of which 12 are previously identified loci in or close to ADCY3, GNPDA2, TMEM18, SEC16B, FAIM2, FTO, TFAP2B, TNNI3K, MC4R, GPR61, LMX1B and OLFM4 associated with adult body mass index or childhood obesity. We identified three novel loci: rs13253111 near ELP3, rs8092503 near RAB27B and rs13387838 near ADAM23. Per additional risk allele, body mass index increased 0.04 Standard Deviation Score (SDS) [Standard Error (SE) 0.007], 0.05 SDS (SE 0.008) and 0.14 SDS (SE 0.025), for rs13253111, rs8092503 and rs13387838, respectively. A genetic risk score combining all 15 SNPs showed that each additional average risk allele was associated with a 0.073 SDS (SE 0.011, P-value = 3.12 × 10−10) increase in childhood body mass index in a population of 1955 children. This risk score explained 2% of the variance in childhood body mass index. This study highlights the shared genetic background between childhood and adult body mass index and adds three novel loci. These loci likely represent age-related differences in strength of the associations with body mass index. Refereed/Peer-reviewed

Recently, the Type 1 Diabetes Genetics Consortium (T1DGC) reported 22 novel type 1 diabetes (T1D)-associated loci identified by meta-analysis of three genome-wide association studies (GWASs) with a case-control design. However, the association of 10 of these 22 reported loci was not confirmed in the T1DGC family cohort (P > 0.1). To address concerns about potential bias from population stratification, this study aims to replicate the association in three independent GWAS cohorts, one of which was based on the stratification-proof transmission disequilibrium analysis. Three European-descent population samples were included in this study: 483 cases and both parents, a case-control cohort of 514 cases and 2027 controls, and an additional cohort of 1078 cases and 341 controls from the dbGaP database. Among the 22 SNPs reported by the T1DGC, we had high-quality genotypes for 15; the remaining were imputed. T1D association was replicated in seven loci after Bonferroni correction for 22 independent hypotheses. An additional eight loci had nominal (one-sided) significance of P < 0.1 in the same direction, giving a false discovery rate of 3.35%. The genetic susceptibility conferred by non-HLA loci in our family cohort with one affected offspring was higher than the T1DGC multiplex families. Reciprocally, the frequency of strongly predisposing HLA alleles in the multiplex families was higher. This study replicated T1D association with at least as many of these novel loci as expected from the power of our sample size, thus supporting the validity of the new discoveries.