The genetics of Crohn’s disease and ulcerative colitis – status quo and beyond

Figures & data

Table I. Large-scale association studies performed in IBD until 11/2014. The table likely misses important studies (mostly after 2010) and solely serves to illustrate that a large number of studies have been performed by many international groups and that sample sizes increased over time.

Year	Technology	Author	Disease	Remarks	Country	GWAS cases	GWAS controls	Replication cases	Replication controls
2005	73k	Yamazaki et al. [63]	CD		Japan	94 CD	752	484 CD	345
2006	Illumina 300k	Duerr et al. [64]	CD	Ileal only	North America	567 CD	571	401 CD; 833 trios	433
2007	Nonsynonymous SNP 20k	Hampe et al. [33]	CD		Germany	735 CD	368	498 CD; 380 trios	1032
2007	Affymetrix 100k	Franke et al. [65]	CD		Germany	393 CD	399	942 CD; 375 trios	1082
2007	Perlegen 165k	Raelson et al. [66]	CD		Canada (Québec founder population); Germany	382 CD		752 CD; 521 trios	828
2007	Illumina 300k	Libioulle et al. [67]	CD		Belgium; France	547 CD	928	1266 HC	559
2007	Affymetrix 500k	WTCCC [68]	CD		UK	1748 CD	2938	1182 CD	2024
2008	Meta-analysis	Barrett et al. [1]	CD		UK/North/America/France/Belgium	3230 CD	4829	2325 CD;1339 trios	1809
2008	Nonsynonymous SNP 14k	Fisher et al. [69]	UC		UK	905 UC	1465	2028 UC	3029
2008	Affymetrix 500k	Franke et al. [27]	UC		Germany	1167 UC	777	1855 UC	3091
2008	Illumina 550k	Kugathasan et al. [70]	IBD	Early-onset	North America; Italy	1011 IBD	4250	173 IBD	3481
2009	Illumina 550k and 300k	Silverberg et al. [71]	UC	No proctitis	North America	1052 UC	2571	1405 UC	1115
2009	Illumina 550k;Affymetrix custom 10k	Asano et al. [72]	UC		Japan	749 UC	2031	635 UC	1026
2009	Affymetrix 1000k	UKIBDGC [73]	UC		UK	2361 UC	5417	2321 UC	4818
2009	Illumina 550k	Imielinski et al. [74]	IBD	Early-onset	North America; Scotland; Italy	1636 CD;724 UC	6158	829 CD; 120 UC	5805
2010	Affymetrix 1000k	Franke et al. [75]	UC		Germany; UK; Belgium; Norway; Greece; Baltic Countries	1043 UC	1703	2539 UC	5428
2010	Illumina 550k	Wang et al. [76]	IBD, T1D	Overlap analysis	European ancestry	1689 CD;777 UC;989 T1D	6197
2010	Meta-analysis	McGovern et al. [77]	UC		North America/Sweden meta-analysis; Italy; Netherlands	2693 UC	6791	2009 UC	1580
2010	Meta-analysis	Franke et al. [2]	CD		European ancestry	6,333 CD	15,056	15,694 CD; 414 trios	14,026
2011	Meta-analysis	Anderson et al. [3]	UC		European ancestry	6,687 UC	19,718	9,628 CD	12,917
2012	Meta-analysis (GWAS and Immunochip data)	Jostins et al. [2]	IBD		European ancestry	5,937 CD; 6,945 UC	21,770	14,763 CD; 10,920 UC	15,977
2012	Illumina 300k/550k, Affymetrix 500k/6.0	Kenny et al. [78]	CD		Ashkenazi Jews	907	2345	971	2124
2013	Illumina Quad610	Julià et al. [79]	CD		South Europe	1341	1518	1365	1396
2013	Illumina HumanHap550	Yamazaki et al. [80]	CD		Japan	372	3389	1151	15800
2014	Illumina OmniExpress/Omni1-Quad arrays	Yang et al. [81]	CD		Korea	533	800	1779	1709
2014	Illumina Quad610	Julià et al. [82]	UC		South Europe	825	1525	1073	1279

Abbreviations: CD = Crohn’s disease; GWAS = Genome-wide association studies; IBD = Inflammatory bowel disease; UC = Ulcerative colitis.

Figure 1. Risk allele frequency versus odds ratio plot. Data for 163 index SNPs were extracted from the latest meta-analysis on inflammatory bowel disease (IBD) [2]. The risk allele frequency is plotted on the X-axis and shows that most identified alleles have a minor allele frequency >5%. Alleles can be protective (risk allele frequency >0.50) or exert risk (<0.50). The Y-axis shows the odds ratio and that almost all identified risk variants have an odds ratio <1.30 (corresponding to >0.77 for protective variants). Colors indicate whether the particular variant reached genome-wide significance for Crohn’s disease (CD) (red), ulcerative colitis (UC) (blue) or both diseases (green). The by far strongest UC-associated locus was the noncoding SNP rs6927022 (p = 4.71 × 10^-133; OR [odds ratio] = 1.44; 95% CI = (1.39–1.50)) near the class I gene HLA-DQA1. However, more relevant UC-associated HLA-DRB1 alleles as DRB1*15:01, DRB1*07:01 and DRB1*01:03 show much larger effect sizes [20].

Figure 2. Inflammatory bowel disease (IBD) etiology as an example for a complex chronic inflammatory disease. In most patients (prevalence illustrated by dashed curve), IBD develops through (mostly unknown) environmental factors – also including the gut microbiome – that act on a genetically predisposed host. Yet, cases have been described where highly penetrant genetic mutations cause (monogenic) IBD. It is still discussed how relevant infections are in the onset of IBD. The gene–environment interactions (red arrows) are important in disease etiology and should be studied in more detail in the future. While genome-wide association studies (GWAS) are successful to identify common disease loci, linkage studies are more powerful to identify monogenic forms of IBD. Recently, exome-sequencing has been employed for these early-onset forms since next-generation sequencing provides single base pair resolution for mutation detection and also allows for de novo mutation detection. Modified from Kaser et al. [83].

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