Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes

Guðmundsson, Jūlı́us; Sulem, Patrick; Steinthórsdóttir, Valgerður; Bergþórsson, Jón Þór; Þorleifsson, Guðmar; Manolescu, Andrei; Rafnar, Thorunn; Guðbjartsson, Daníel F.; Agnarsson, Bjarni A.; Baker, Adam; Sigurðsson, Ásgeir; Benediktsdóttir, Kristrún R.; Jakobsdottir, Margret; Blöndal, Thórarinn; Stacey, Simon; Helgason, Agnar; Gunnarsdóttir, Steinunn; Ólafsdóttir, Aðalheiður; Kristinsson, Kári; Birgisdottir, Birgitta; Ghosh, Shyamali; Thorlacius, Steinunn; Magnusdottir, Dana; Stefánsdóttir, Gerður; Kristjánsson, Kristleifur; Bagger, Yu Z.; Wilensky, Robert L.; Reilly, Muredach P.; Morris, Andrew D.; Kimber, Charlotte H.; Adeyemo, Adebowale; Chen, Yuanxiu; Zhou, Jie; So, Wing Yee; Tong, Peter C.Y.; Ng, Maggie; Hansen, Torben; Andersen, Gitte; Borch‐Johnsen, Knut; Jørgensen, Torben; Trés, A.; Fuertes, Fernando; Ruiz-Echarri, Manuel; Asín, Laura; Sáez, Berta; Boven, Erica van; Klaver, Siem M.; Swinkels, Dorine W.; Aben, Katja K.H.; Graif, Theresa; Cashy, John; Suarez, Brian K.; Trip, Onco Van Vierssen; Frigge, Michael L.; Ober, Carole; Hofker, Marten H.; Wijmenga, Cisca; Christiansen, Claus; Rader, Daniel J.; Palmer, Colin N.A.; Rotimi, Charles N.; Chan, Juliana C.N.; Pedersen, Oluf; Sigurðsson, Gunnar; Benediktsson, Rafn; Jónsson, Eiríkur; Einarsson, Guðmundur; Mayordomo, J. I.; Catàlona, William J.; Kiemeney, Lambertus A.; Barkardóttir, Rósa B.; Gulcher, Jeffrey R.; Þorsteinsdóttir, Unnur; Kong, Augustine; Stefánsson, Kāri

doi:10.1038/ng2062

Cited by 666 publications

(489 citation statements)

References 21 publications

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“…Curiously, some of the recent studies suggest a possible explanation for previous much debated epidemiological observations that men with T2D are less likely to develop prostate cancer. The same allele in HNF1B (or TCF2) that predisposes to T2DM was protective of prostate cancer (80). Moreover, different variants in JAZF1 are associated with T2D and with prostate cancer (34)(35)(36)81).…”

Section: Whole Genome Association Studiesmentioning

confidence: 98%

Genetic dissection of type 2 diabetes

Ridderstråle¹,

Groop²

2009

Molecular and Cellular Endocrinology

123

114

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Compared to the successful probing of genetic causes of monogenic disorders, dissecting the genetics of complex polygenic diseases has until recently been a fairly slow and cumbersome process. With the introduction of whole genome wide association studies (WGAS) the situation dramatically changed in 2007. The results from several recent WGAS on type 2 diabetes (T2D) and obesity have identified at least eighteen genes consistently associated with T2D. Many of the genes implicate pancreatic beta-cell function in the pathogenesis of T2D whereas only one clearly associate with insulin resistance. The identified genes most likely merely represent the tip of the iceberg in the explanation behind T2D. Refined tools will have to provide a more complete picture of the genetic complexity of T2D over the next few years. In addition to common variants increasing susceptibility for the disease, rare variants with stronger effects, copy number variations, and epigenetic effects like DNA methylation and histone acetylation will become important. Nevertheless, today we are able for the first time to anticipate that the genetics of a complex disease like T2D really can be dissected. Key wordsgenetics, complex disease, monogenic, polygenic, linkage study, genome wide scan, association study, single nucleotide polymorphism, epigenetic, type 2 diabetes, obesity. Evidence that type 2 diabetes is inheritedThere is ample evidence that T2D has a strong genetic component. The concordance of T2D in monozygotic twins is approximately 70% compared with 20-30% in dizygotic twins (1,2). Given the age-dependent penetrance of the disease, it is clear that the longer the follow-up, the higher the concordance rate (2). T2D clusters in families. The life-time risk of developing the disease is about 40% in offspring of one parent with T2D (3), greater if the mother is affected (4), the risk approaching 70% if both parents have diabetes. Translated into a s-value, the recurrence risk for a sibling of an affected person divided by the risk for the general population, this means that a first-degree relative of a patient with type 2 diabetes has a 3-fold increased risk of developing the disease (5). Large ethnic differences in the prevalence of T2D have also been ascribed to a genetic component (6,7). The change in the environment towards a more affluent Western life style plays a key role in the epidemic increase in the prevalence of T2Dworldwide. This change has occurred during the last 50 years. Clearly, our genes have not changed during this period but this does not exclude an important role for genes in the rapid increase in T2D, since genes or gene variants explain how we respond to the environment. Page 4 of 25A c c e p t e d M a n u s c r i p t 4 Thrifty genotypes or phenotypes?A plausible explanation for the interaction between genes and environment comes from the thrifty gene hypothesis. Neel (8) proposed that individuals living in an environment with unstable food supply (as for hunters and nomads) would maximize their probabilit...

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Section: Whole Genome Association Studiesmentioning

confidence: 98%

Genetic dissection of type 2 diabetes

Ridderstråle¹,

Groop²

2009

Molecular and Cellular Endocrinology

123

114

View full text Add to dashboard Cite

show abstract

“…[1][2][3][4][5][6][7][8][9][10] One of the current major challenges is to understand the underlying biology behind these association signals. Unlike most genetic effectors of Mendelian diseases, the majority of GWAS-discovered risk variants tend to lie within intronic, intergenic, or gene desert regions.…”

Section: Introductionmentioning

confidence: 99%

Variants at IRX4 as prostate cancer expression quantitative trait loci

Hussain

Vijai

et al. 2013

Eur J Hum Genet

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Genome-wide association studies (GWAS) have identified numerous prostate cancer-associated risk loci. Some variants at these loci may be regulatory and influence expression of nearby genes. Such loci are known as cis-expression quantitative trait loci (cis-eQTL). As cis-eQTLs are highly tissue-specific, we asked if GWAS-identified prostate cancer risk loci are cis-eQTLs in human prostate tumor tissues. We investigated 50 prostate cancer samples for their genotype at 59 prostate cancer riskassociated single-nucleotide polymorphisms (SNPs) and performed cis-eQTL analysis of transcripts from paired primary tumors within two megabase windows. We tested 586 transcript-genotype associations, of which 27 were significant (false discovery rate r10%). An equivalent eQTL analysis of the same prostate cancer risk loci in lymphoblastoid cell lines did not result in any significant associations. The top-ranked cis-eQTL involved the IRX4 (Iroquois homeobox protein 4) transcript and rs12653946, tagged by rs10866528 in our study (P ¼ 4.91 Â 10 À5 ). Replication studies, linkage disequilibrium, and imputation analyses highlight population specificity at this locus. We independently validated IRX4 as a potential prostate cancer risk gene through cis-eQTL analysis of prostate cancer risk variants. Cis-eQTL analysis in relevant tissues, even with a small sample size, can be a powerful method to expedite functional follow-up of GWAS.

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“…More interestingly, the variant in TCF2 increased the risk of prostate cancer but protective against T2D. 80 This is one of the first examples from GWAS showing a genetic variant having opposing actions on two different diseases. SNPs in 9p21 locus were also found to be associated with various cancers, in addition to cardiovascular diseases and T2D.…”

Section: The Recent 2 Years: 2008 and 2009mentioning

confidence: 90%

The pursuit of genome-wide association studies: where are we now?

et al. 2010

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It is now 5 years since the first genome-wide association studies (GWAS), published in 2005, identified a common risk allele with large effect size for age-related macular degeneration in a small sample set. Following this exciting finding, researchers have become optimistic about the prospect of the genome-wide association approach. However, most of the risk alleles identified in the subsequent GWAS for various complex diseases are common with small effect sizes (odds ratio o1.5). So far, more than 450 GWAS have been published and the associations of greater than 2000 single nucleotide polymorphisms (SNPs) or genetic loci were reported. The aim of this review paper is to give an overview of the evolving field of GWAS, discuss the progress that has been made by GWAS and some of the interesting findings, and summarize what we have learned over the past 5 years about the genetic basis of human complex diseases. This review will focus on GWAS of SNPs association for complex diseases but not studies of copy number variations.

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Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes

Cited by 666 publications

References 21 publications

Genetic dissection of type 2 diabetes

Genetic dissection of type 2 diabetes

Variants at IRX4 as prostate cancer expression quantitative trait loci

The pursuit of genome-wide association studies: where are we now?

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