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1.  Genome-wide association study identifies a sequence variant within the DAB2IP gene conferring susceptibility to abdominal aortic aneurysm 
Gretarsdottir, Solveig | Baas, Annette F | Thorleifsson, Gudmar | Holm, Hilma | den Heijer, Martin | de Vries, Jean-Paul P M | Kranendonk, Steef E | Zeebregts, Clark J A M | van Sterkenburg, Steven M | Geelkerken, Robert H | van Rij, Andre M | Williams, Michael J A | Boll, Albert P M | Kostic, Jelena P | Jonasdottir, Adalbjorg | Jonasdottir, Aslaug | Walters, G Bragi | Masson, Gisli | Sulem, Patrick | Saemundsdottir, Jona | Mouy, Magali | Magnusson, Kristinn P | Tromp, Gerard | Elmore, James R | Sakalihasan, Natzi | Limet, Raymond | Defraigne, Jean-Olivier | Ferrell, Robert E | Ronkainen, Antti | Ruigrok, Ynte M | Wijmenga, Cisca | Grobbee, Diederick E | Shah, Svati H | Granger, Christopher B | Quyyumi, Arshed A | Vaccarino, Viola | Patel, Riyaz S | Zafari, A Maziar | Levey, Allan I | Austin, Harland | Girelli, Domenico | Pignatti, Pier Franco | Olivieri, Oliviero | Martinelli, Nicola | Malerba, Giovanni | Trabetti, Elisabetta | Becker, Lewis C | Becker, Diane M | Reilly, Muredach P | Rader, Daniel J | Mueller, Thomas | Dieplinger, Benjamin | Haltmayer, Meinhard | Urbonavicius, Sigitas | Lindblad, Bengt | Gottsäter, Anders | Gaetani, Eleonora | Pola, Roberto | Wells, Philip | Rodger, Marc | Forgie, Melissa | Langlois, Nicole | Corral, Javier | Vicente, Vicente | Fontcuberta, Jordi | España, Francisco | Grarup, Niels | Jørgensen, Torben | Witte, Daniel R | Hansen, Torben | Pedersen, Oluf | Aben, Katja K | de Graaf, Jacqueline | Holewijn, Suzanne | Folkersen, Lasse | Franco-Cereceda, Anders | Eriksson, Per | Collier, David A | Stefansson, Hreinn | Steinthorsdottir, Valgerdur | Rafnar, Thorunn | Valdimarsson, Einar M | Magnadottir, Hulda B | Sveinbjornsdottir, Sigurlaug | Olafsson, Isleifur | Magnusson, Magnus Karl | Palmason, Robert | Haraldsdottir, Vilhelmina | Andersen, Karl | Onundarson, Pall T | Thorgeirsson, Gudmundur | Kiemeney, Lambertus A | Powell, Janet T | Carey, David J | Kuivaniemi, Helena | Lindholt, Jes S | Jones, Gregory T | Kong, Augustine | Blankensteijn, Jan D | Matthiasson, Stefan E | Thorsteinsdottir, Unnur | Stefansson, Kari
Nature genetics  2010;42(8):692-697.
We performed a genome-wide association study on 1,292 individuals with abdominal aortic aneurysms (AAAs) and 30,503 controls from Iceland and The Netherlands, with a follow-up of top markers in up to 3,267 individuals with AAAs and 7,451 controls. The A allele of rs7025486 on 9q33 was found to associate with AAA, with an odds ratio (OR) of 1.21 and P = 4.6 × 10−10. In tests for association with other vascular diseases, we found that rs7025486[A] is associated with early onset myocardial infarction (OR = 1.18, P = 3.1 × 10−5), peripheral arterial disease (OR = 1.14, P = 3.9 × 10−5) and pulmonary embolism (OR = 1.20, P = 0.00030), but not with intracranial aneurysm or ischemic stroke. No association was observed between rs7025486[A] and common risk factors for arterial and venous diseases—that is, smoking, lipid levels, obesity, type 2 diabetes and hypertension. Rs7025486 is located within DAB2IP, which encodes an inhibitor of cell growth and survival.
doi:10.1038/ng.622
PMCID: PMC4157066  PMID: 20622881
2.  Loss-of-function mutations in SLC30A8 protect against type 2 diabetes 
Flannick, Jason | Thorleifsson, Gudmar | Beer, Nicola L. | Jacobs, Suzanne B. R. | Grarup, Niels | Burtt, Noël P. | Mahajan, Anubha | Fuchsberger, Christian | Atzmon, Gil | Benediktsson, Rafn | Blangero, John | Bowden, Don W. | Brandslund, Ivan | Brosnan, Julia | Burslem, Frank | Chambers, John | Cho, Yoon Shin | Christensen, Cramer | Douglas, Desirée A. | Duggirala, Ravindranath | Dymek, Zachary | Farjoun, Yossi | Fennell, Timothy | Fontanillas, Pierre | Forsén, Tom | Gabriel, Stacey | Glaser, Benjamin | Gudbjartsson, Daniel F. | Hanis, Craig | Hansen, Torben | Hreidarsson, Astradur B. | Hveem, Kristian | Ingelsson, Erik | Isomaa, Bo | Johansson, Stefan | Jørgensen, Torben | Jørgensen, Marit Eika | Kathiresan, Sekar | Kong, Augustine | Kooner, Jaspal | Kravic, Jasmina | Laakso, Markku | Lee, Jong-Young | Lind, Lars | Lindgren, Cecilia M | Linneberg, Allan | Masson, Gisli | Meitinger, Thomas | Mohlke, Karen L | Molven, Anders | Morris, Andrew P. | Potluri, Shobha | Rauramaa, Rainer | Ribel-Madsen, Rasmus | Richard, Ann-Marie | Rolph, Tim | Salomaa, Veikko | Segrè, Ayellet V. | Skärstrand, Hanna | Steinthorsdottir, Valgerdur | Stringham, Heather M. | Sulem, Patrick | Tai, E Shyong | Teo, Yik Ying | Teslovich, Tanya | Thorsteinsdottir, Unnur | Trimmer, Jeff K. | Tuomi, Tiinamaija | Tuomilehto, Jaakko | Vaziri-Sani, Fariba | Voight, Benjamin F. | Wilson, James G. | Boehnke, Michael | McCarthy, Mark I. | Njølstad, Pål R. | Pedersen, Oluf | Groop, Leif | Cox, David R. | Stefansson, Kari | Altshuler, David
Nature genetics  2014;46(4):357-363.
Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets1,2,3, yet none are described for type 2 diabetes (T2D). Through sequencing or genotyping ~150,000 individuals across five ethnicities, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8)4 and harbors a common variant (p.Trp325Arg) associated with T2D risk, glucose, and proinsulin levels5–7. Collectively, protein-truncating variant carriers had 65% reduced T2D risk (p=1.7×10−6), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34SerfsX50) demonstrated reduced glucose levels (−0.17 s.d., p=4.6×10−4). The two most common protein-truncating variants (p.Arg138X and p.Lys34SerfsX50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested reduced zinc transport increases T2D risk8,9, yet phenotypic heterogeneity was observed in rodent Slc30a8 knockouts10–15. Contrastingly, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, proposing ZnT8 inhibition as a therapeutic strategy in T2D prevention.
doi:10.1038/ng.2915
PMCID: PMC4051628  PMID: 24584071
3.  Germline sequence variants in TGM3 and RGS22 confer risk of basal cell carcinoma 
Human Molecular Genetics  2014;23(11):3045-3053.
To search for new sequence variants that confer risk of cutaneous basal cell carcinoma (BCC), we conducted a genome-wide association study of 38.5 million single nucleotide polymorphisms (SNPs) and small indels identified through whole-genome sequencing of 2230 Icelanders. We imputed genotypes for 4208 BCC patients and 109 408 controls using Illumina SNP chip typing data, carried out association tests and replicated the findings in independent population samples. We found new BCC susceptibility loci at TGM3 (rs214782[G], P = 5.5 × 10−17, OR = 1.29) and RGS22 (rs7006527[C], P = 8.7 × 10−13, OR = 0.77). TGM3 encodes transglutaminase type 3, which plays a key role in production of the cornified envelope during epidermal differentiation.
doi:10.1093/hmg/ddt671
PMCID: PMC4014188  PMID: 24403052
4.  Common Variant at 16p11.2 Conferring Risk of Psychosis 
Steinberg, Stacy | de Jong, Simone | Mattheisen, Manuel | Costas, Javier | Demontis, Ditte | Jamain, Stéphane | Pietiläinen, Olli P H | Lin, Kuang | Papiol, Sergi | Huttenlocher, Johanna | Sigurdsson, Engilbert | Vassos, Evangelos | Giegling, Ina | Breuer, René | Fraser, Gillian | Walker, Nicholas | Melle, Ingrid | Djurovic, Srdjan | Agartz, Ingrid | Tuulio-Henriksson, Annamari | Suvisaari, Jaana | Lönnqvist, Jouko | Paunio, Tiina | Olsen, Line | Hansen, Thomas | Ingason, Andres | Pirinen, Matti | Strengman, Eric | Hougaard, David M | Ørntoft, Torben | Didriksen, Michael | Hollegaard, Mads V | Nordentoft, Merete | Abramova, Lilia | Kaleda, Vasily | Arrojo, Manuel | Sanjuán, Julio | Arango, Celso | Etain, Bruno | Bellivier, Frank | Méary, Alexandre | Schürhoff, Franck | Szoke, Andrei | Ribolsi, Michele | Magni, Valentina | Siracusano, Alberto | Sperling, Swetlana | Rossner, Moritz | Christiansen, Claus | Kiemeney, Lambertus A | Franke, Barbara | van den Berg, Leonard H | Veldink, Jan | Curran, Sarah | Bolton, Patrick | Poot, Martin | Staal, Wouter | Rehnstrom, Karola | Kilpinen, Helena | Freitag, Christine M | Meyer, Jobst | Magnusson, Pall | Saemundsen, Evald | Martsenkovsky, Igor | Bikshaieva, Iana | Martsenkovska, Inna | Vashchenko, Olesya | Raleva, Marija | Paketchieva, Kamka | Stefanovski, Branislav | Durmishi, Naser | Milovancevic, Milica Pejovic | Tosevski, Dusica Lecic | Silagadze, Teimuraz | Naneishvili, Nino | Mikeladze, Nina | Surguladze, Simon | Vincent, John B | Farmer, Anne | Mitchell, Philip B | Wright, Adam | Schofield, Peter R | Fullerton, Janice M | Montgomery, Grant W | Martin, Nicholas G | Rubino, I Alex | van Winkel, Ruud | Kenis, Gunter | De Hert, Marc | Réthelyi, János M | Bitter, István | Terenius, Lars | Jönsson, Erik G | Bakker, Steven | van Os, Jim | Jablensky, Assen | Leboyer, Marion | Bramon, Elvira | Powell, John | Murray, Robin | Corvin, Aiden | Gill, Michael | Morris, Derek | O’Neill, F Anthony | Kendler, Ken | Riley, Brien | Craddock, Nick | Owen, Michael J | O’Donovan, Michael C | Thorsteinsdottir, Unnur | Kong, Augustine | Ehrenreich, Hannelore | Carracedo, Angel | Golimbet, Vera | Andreassen, Ole A | Børglum, Anders D | Mors, Ole | Mortensen, Preben B | Werge, Thomas | Ophoff, Roel A | Nöthen, Markus M | Rietschel, Marcella | Cichon, Sven | Ruggeri, Mirella | Tosato, Sarah | Palotie, Aarno | St Clair, David | Rujescu, Dan | Collier, David A | Stefansson, Hreinn | Stefansson, Kari
Molecular psychiatry  2012;19(1):10.1038/mp.2012.157.
Epidemiological and genetic data support the notion that schizophrenia and bipolar disorder share genetic risk factors. In our previous genome-wide association (GWA) study, meta-analysis and follow-up (totaling as many as 18,206 cases and 42,536 controls), we identified four loci showing genome-wide significant association with schizophrenia. Here we consider a mixed schizophrenia and bipolar disorder (psychosis) phenotype (addition of 7,469 bipolar disorder cases, 1,535 schizophrenia cases, 333 other psychosis cases, 808 unaffected family members and 46,160 controls). Combined analysis reveals a novel variant at 16p11.2 showing genome-wide significant association (rs4583255[T], OR = 1.08, P = 6.6 × 10−11). The new variant is located within a 593 kb region that substantially increases risk of psychosis when duplicated. In line with the association of the duplication with reduced body mass index (BMI), rs4583255[T] is also associated with lower BMI (P = 0.0039 in the public GIANT consortium dataset; P = 0.00047 in 22,651 additional Icelanders).
doi:10.1038/mp.2012.157
PMCID: PMC3872086  PMID: 23164818
schizophrenia; bipolar disorder; association; 16p11.2; cross-disorder
5.  Mapping cis- and trans-regulatory effects across multiple tissues in twins 
Nature genetics  2012;44(10):1084-1089.
Sequence-based variation in gene expression is a key driver of disease risk. Common variants regulating expression in cis have been mapped in many eQTL studies typically in single tissues from unrelated individuals. Here, we present a comprehensive analysis of gene expression across multiple tissues conducted in a large set of mono- and dizygotic twins that allows systematic dissection of genetic (cis and trans) and non-genetic effects on gene expression. Using identity-by-descent estimates, we show that at least 40% of the total heritable cis-effect on expression cannot be accounted for by common cis-variants, a finding which exposes the contribution of low frequency and rare regulatory variants with respect to both transcriptional regulation and complex trait susceptibility. We show that a substantial proportion of gene expression heritability is trans to the structural gene and identify several replicating trans-variants which act predominantly in a tissue-restricted manner and may regulate the transcription of many genes.
doi:10.1038/ng.2394
PMCID: PMC3784328  PMID: 22941192
6.  Parental origin of sequence variants associated with complex diseases 
Nature  2009;462(7275):868-874.
Effects of susceptibility variants may depend on from which parent they are inherited. While many associations between sequence variants and human traits have been discovered through genome-wide associations, the impact of parental origin has largely been ignored. Combining genealogy with long range phasing, we demonstrate that for 38,167 Icelanders genotyped using SNP chips, the parental origin of most alleles can be determined. We then focused on SNPs that associate with diseases and are within 500kb of known imprinted genes. Seven independent SNP associations were examined. Five, one each with breast cancer and basal cell carcinoma, and three with type 2 diabetes (T2D), exhibit parental-origin specific associations. These variants are located in two genomic regions, 11p15 and 7q32, each harbouring a cluster of imprinted genes. Furthermore, a novel variant rs2334499 at 11p15 was seen to associate with T2D where the allele that confers risk when paternally inherited is protective when maternally transmitted. We identified a differentially methylated CTCF binding site at 11p15 and demonstrated correlation of rs2334499 with decreased methylation of that site.
doi:10.1038/nature08625
PMCID: PMC3746295  PMID: 20016592
7.  Variant in the sequence of the LINGO1 gene confers risk of essential tremor 
Nature genetics  2009;41(3):277-279.
We identified a marker in LINGO1 showing genome-wide significant association (P = 1.2 × 10−9, odds ratio = 1.55) with essential tremor. LINGO1 has potent, negative regulatory influences on neuronal survival and is also important in regulating both central-nervous-system axon regeneration and oligodendrocyte maturation. An increase in the number of fusiform swellings of Purkinje cell axons in LINGO1 knockout models highlights the potential role of LINGO1 in essential tremor pathophysiology.
doi:10.1038/ng.299
PMCID: PMC3740956  PMID: 19182806
8.  Variant of TREM2 Associated with the Risk of Alzheimer’s Disease 
The New England journal of medicine  2012;368(2):107-116.
BACKGROUND
Sequence variants, including the ε4 allele of apolipoprotein E, have been associated with the risk of the common late-onset form of Alzheimer’s disease. Few rare variants affecting the risk of late-onset Alzheimer’s disease have been found.
METHODS
We obtained the genome sequences of 2261 Icelanders and identified sequence variants that were likely to affect protein function. We imputed these variants into the genomes of patients with Alzheimer’s disease and control participants and then tested for an association with Alzheimer’s disease. We performed replication tests using case–control series from the United States, Norway, the Netherlands, and Germany. We also tested for a genetic association with cognitive function in a population of unaffected elderly persons.
RESULTS
A rare missense mutation (rs75932628-T) in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2), which was predicted to result in an R47H substitution, was found to confer a significant risk of Alzheimer’s disease in Iceland (odds ratio, 2.92; 95% confidence interval [CI], 2.09 to 4.09; P = 3.42×10−10). The mutation had a frequency of 0.46% in controls 85 years of age or older. We observed the association in additional sample sets (odds ratio, 2.90; 95% CI, 2.16 to 3.91; P = 2.1×10−12 in combined discovery and replication samples). We also found that carriers of rs75932628-T between the ages of 80 and 100 years without Alzheimer’s disease had poorer cognitive function than noncarriers (P = 0.003).
CONCLUSIONS
Our findings strongly implicate variant TREM2 in the pathogenesis of Alzheimer’s disease. Given the reported antiinflammatory role of TREM2 in the brain, the R47H substitution may lead to an increased predisposition to Alzheimer’s disease through impaired containment of inflammatory processes. (Funded by the National Institute on Aging and others.)
doi:10.1056/NEJMoa1211103
PMCID: PMC3677583  PMID: 23150908
9.  Genetic Architecture of Vitamin B12 and Folate Levels Uncovered Applying Deeply Sequenced Large Datasets 
PLoS Genetics  2013;9(6):e1003530.
Genome-wide association studies have mainly relied on common HapMap sequence variations. Recently, sequencing approaches have allowed analysis of low frequency and rare variants in conjunction with common variants, thereby improving the search for functional variants and thus the understanding of the underlying biology of human traits and diseases. Here, we used a large Icelandic whole genome sequence dataset combined with Danish exome sequence data to gain insight into the genetic architecture of serum levels of vitamin B12 (B12) and folate. Up to 22.9 million sequence variants were analyzed in combined samples of 45,576 and 37,341 individuals with serum B12 and folate measurements, respectively. We found six novel loci associating with serum B12 (CD320, TCN2, ABCD4, MMAA, MMACHC) or folate levels (FOLR3) and confirmed seven loci for these traits (TCN1, FUT6, FUT2, CUBN, CLYBL, MUT, MTHFR). Conditional analyses established that four loci contain additional independent signals. Interestingly, 13 of the 18 identified variants were coding and 11 of the 13 target genes have known functions related to B12 and folate pathways. Contrary to epidemiological studies we did not find consistent association of the variants with cardiovascular diseases, cancers or Alzheimer's disease although some variants demonstrated pleiotropic effects. Although to some degree impeded by low statistical power for some of these conditions, these data suggest that sequence variants that contribute to the population diversity in serum B12 or folate levels do not modify the risk of developing these conditions. Yet, the study demonstrates the value of combining whole genome and exome sequencing approaches to ascertain the genetic and molecular architectures underlying quantitative trait associations.
Author Summary
Genome-wide association studies have in recent years revealed a wealth of common variants associated with common diseases and phenotypes. We took advantage of the advances in sequencing technologies to study the association of low frequency and rare variants in conjunction with common variants with serum levels of vitamin B12 (B12) and folate in Icelanders and Danes. We found 18 independent signals in 13 loci associated with serum B12 or folate levels. Interestingly, 13 of the 18 identified variants are coding and 11 of the 13 target genes have known functions related to B12 and folate pathways. These data indicate that the target genes at all of the loci have been identified. Epidemiological studies have shown a relationship between serum B12 and folate levels and the risk of cardiovascular diseases, cancers, and Alzheimer's disease. We investigated association between the identified variants and these diseases but did not find consistent association.
doi:10.1371/journal.pgen.1003530
PMCID: PMC3674994  PMID: 23754956
10.  A study based on whole-genome sequencing yields a rare variant at 8q24 associated with prostate cancer 
Nature genetics  2012;44(12):1326-1329.
Western countries, prostate cancer is the most prevalent cancer of men, and one of the leading causes of cancer-related death in men. Several genome-wide association studies have yielded numerous common variants conferring risk of prostate cancer. In the present study we analyzed 32.5 million variants discovered by whole-genome sequencing 1,795 Icelanders. One variant was found to be associated with prostate cancer in European populations: rs188140481[A] (OR = 2.90, Pcomb = 6.2×10−34) located on 8q24, with an average risk allele control frequency of 0.54%. This variant is only very weakly correlated (r2 ≤ 0.06) with previously reported risk variants on 8q24, and remains significant after adjustment for all of them. Carriers of rs188140481[A] were diagnosed with prostate cancer 1.26 years younger than non-carriers (P = 0.0059). We also report results for the previously described HOXB13 mutation (rs138213197[T]), confirming it as prostate cancer risk variant in populations from all over Europe.
doi:10.1038/ng.2437
PMCID: PMC3562711  PMID: 23104005
11.  Common variants on 9q22.33 and 14q13.3 predispose to thyroid cancer in European populations 
Nature genetics  2009;41(4):460-464.
In order to search for sequence variants conferring risk of thyroid cancer we conducted a genome-wide association study in 192 and 37,196 Icelandic cases and controls, respectively, followed by a replication study in individuals of European descent. Here we show that two common variants, located on 9q22.33 and 14q13.3, are associated with the disease. Overall, the strongest association signals were observed for rs965513 on 9q22.33 (OR = 1.75; P = 1.7 × 10−27) and rs944289 on 14q13.3 (OR = 1.37; P = 2.0 × 10−9). The gene nearest to the 9q22.33 locus is FOXE1 (TTF2) and NKX2-1 (TTF1) is among the genes located at the 14q13.3 locus. Both variants contribute to an increased risk of both papillary and follicular thyroid cancer. Approximately 3.7% of individuals are homozygous for both variants, and their estimated risk of thyroid cancer is 5.7-fold greater than that of noncarriers. In a study on a large sample set from the general population, both risk alleles are associated with low concentrations of thyroid stimulating hormone (TSH), and the 9q22.33 allele is associated with low concentration of thyroxin (T4) and high concentration of triiodothyronine (T3).
doi:10.1038/ng.339
PMCID: PMC3664837  PMID: 19198613
12.  Discovery of common variants associated with low TSH levels and thyroid cancer risk 
Nature genetics  2012;44(3):319-322.
To search for sequence variants conferring risk of nonmedullary thyroid cancer, we focused our analysis on 22 SNPs with a P < 5 × 10−8 in a genome-wide association study on levels of thyroid stimulating hormone (TSH) in 27,758 Icelanders. Of those, rs965513 has previously been shown to associate with thyroid cancer. The remaining 21 SNPs were genotyped in 561 Icelandic individuals with thyroid cancer (cases) and up to 40,013 controls. Variants suggestively associated with thyroid cancer (P < 0.05) were genotyped in an additional 595 non-Icelandic cases and 2,604 controls. After combining the results, three variants were shown to associate with thyroid cancer: rs966423 on 2q35 (OR = 1.34; Pcombined = 1.3 × 10−9), rs2439302 on 8p12 (OR = 1.36; Pcombined = 2.0 × 10−9) and rs116909374 on 14q13.3 (OR = 2.09; Pcombined = 4.6 × 10−11), a region previously reported to contain an uncorrelated variant conferring risk of thyroid cancer. A strong association (P = 9.1 × 10−91) was observed between rs2439302 on 8p12 and expression of NRG1, which encodes the signaling protein neuregulin 1, in blood.
doi:10.1038/ng.1046
PMCID: PMC3655412  PMID: 22267200
13.  A direct characterization of human mutation based on microsatellites 
Nature genetics  2012;44(10):1161-1165.
Mutations are the raw material of evolution, but have been difficult to study directly. We report the largest study of new mutations to date: 2,058 germline changes discovered by analyzing 85,289 Icelanders at 2,477 microsatellites. The paternal-to-maternal mutation rate ratio is 3.3, and the rate in fathers doubles from age 20 to 58 whereas there is no association with age in mothers. Longer microsatellite alleles are more mutagenic and tend to decrease in length, whereas the opposite is seen for shorter alleles. We use these empirical observations to build a model that we apply to individuals for whom we have both genome sequence and microsatellite data, allowing us to estimate key parameters of evolution without calibration to the fossil record. We infer that the sequence mutation rate is 1.4–2.3×10−8 per base pair per generation (90% credible interval), and that human-chimpanzee speciation occurred 3.7–6.6 million years ago.
doi:10.1038/ng.2398
PMCID: PMC3459271  PMID: 22922873
14.  Common sequence variants on 2p15 and Xp11.22 confer susceptibility to prostate cancer 
Gudmundsson, Julius | Sulem, Patrick | Rafnar, Thorunn | Bergthorsson, Jon T | Manolescu, Andrei | Gudbjartsson, Daniel | Agnarsson, Bjarni A | Sigurdsson, Asgeir | Benediktsdottir, Kristrun R | Blondal, Thorarinn | Jakobsdottir, Margret | Stacey, Simon N | Kostic, Jelena | Kristinsson, Kari T | Birgisdottir, Birgitta | Ghosh, Shyamali | Magnusdottir, Droplaug N | Thorlacius, Steinunn | Thorleifsson, Gudmar | Zheng, S Lilly | Sun, Jielin | Chang, Bao-Li | Elmore, J Bradford | Breyer, Joan P | McReynolds, Kate M | Bradley, Kevin M | Yaspan, Brian L | Wiklund, Fredrik | Stattin, Par | Lindström, Sara | Adami, Hans-Olov | McDonnell, Shannon K | Schaid, Daniel J | Cunningham, Julie M | Wang, Liang | Cerhan, James R | St Sauver, Jennifer L | Isaacs, Sara D | Wiley, Kathleen E | Partin, Alan W | Walsh, Patrick C | Polo, Sonia | Ruiz-Echarri, Manuel | Navarrete, Sebastian | Fuertes, Fernando | Saez, Berta | Godino, Javier | Weijerman, Philip C | Swinkels, Dorine W | Aben, Katja K | Witjes, J Alfred | Suarez, Brian K | Helfand, Brian T | Frigge, Michael L | Kristjansson, Kristleifur | Ober, Carole | Jonsson, Eirikur | Einarsson, Gudmundur V | Xu, Jianfeng | Gronberg, Henrik | Smith, Jeffrey R | Thibodeau, Stephen N | Isaacs, William B | Catalona, William J | Mayordomo, Jose I | Kiemeney, Lambertus A | Barkardottir, Rosa B | Gulcher, Jeffrey R | Thorsteinsdottir, Unnur | Kong, Augustine | Stefansson, Kari
Nature genetics  2008;40(3):281-283.
We conducted a genome-wide SNP association study on prostate cancer on over 23,000 Icelanders, followed by a replication study including over 15,500 individuals from Europe and the United States. Two newly identified variants were shown to be associated with prostate cancer: rs5945572 on Xp11.22 and rs721048 on 2p15 (odds ratios (OR) = 1.23 and 1.15; P = 3.9 × 10−13 and 7.7 × 10−9, respectively). The 2p15 variant shows a significantly stronger association with more aggressive, rather than less aggressive, forms of the disease.
doi:10.1038/ng.89
PMCID: PMC3598012  PMID: 18264098
15.  Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways 
Scott, Robert A | Lagou, Vasiliki | Welch, Ryan P | Wheeler, Eleanor | Montasser, May E | Luan, Jian’an | Mägi, Reedik | Strawbridge, Rona J | Rehnberg, Emil | Gustafsson, Stefan | Kanoni, Stavroula | Rasmussen-Torvik, Laura J | Yengo, Loïc | Lecoeur, Cecile | Shungin, Dmitry | Sanna, Serena | Sidore, Carlo | Johnson, Paul C D | Jukema, J Wouter | Johnson, Toby | Mahajan, Anubha | Verweij, Niek | Thorleifsson, Gudmar | Hottenga, Jouke-Jan | Shah, Sonia | Smith, Albert V | Sennblad, Bengt | Gieger, Christian | Salo, Perttu | Perola, Markus | Timpson, Nicholas J | Evans, David M | Pourcain, Beate St | Wu, Ying | Andrews, Jeanette S | Hui, Jennie | Bielak, Lawrence F | Zhao, Wei | Horikoshi, Momoko | Navarro, Pau | Isaacs, Aaron | O’Connell, Jeffrey R | Stirrups, Kathleen | Vitart, Veronique | Hayward, Caroline | Esko, Tönu | Mihailov, Evelin | Fraser, Ross M | Fall, Tove | Voight, Benjamin F | Raychaudhuri, Soumya | Chen, Han | Lindgren, Cecilia M | Morris, Andrew P | Rayner, Nigel W | Robertson, Neil | Rybin, Denis | Liu, Ching-Ti | Beckmann, Jacques S | Willems, Sara M | Chines, Peter S | Jackson, Anne U | Kang, Hyun Min | Stringham, Heather M | Song, Kijoung | Tanaka, Toshiko | Peden, John F | Goel, Anuj | Hicks, Andrew A | An, Ping | Müller-Nurasyid, Martina | Franco-Cereceda, Anders | Folkersen, Lasse | Marullo, Letizia | Jansen, Hanneke | Oldehinkel, Albertine J | Bruinenberg, Marcel | Pankow, James S | North, Kari E | Forouhi, Nita G | Loos, Ruth J F | Edkins, Sarah | Varga, Tibor V | Hallmans, Göran | Oksa, Heikki | Antonella, Mulas | Nagaraja, Ramaiah | Trompet, Stella | Ford, Ian | Bakker, Stephan J L | Kong, Augustine | Kumari, Meena | Gigante, Bruna | Herder, Christian | Munroe, Patricia B | Caulfield, Mark | Antti, Jula | Mangino, Massimo | Small, Kerrin | Miljkovic, Iva | Liu, Yongmei | Atalay, Mustafa | Kiess, Wieland | James, Alan L | Rivadeneira, Fernando | Uitterlinden, Andre G | Palmer, Colin N A | Doney, Alex S F | Willemsen, Gonneke | Smit, Johannes H | Campbell, Susan | Polasek, Ozren | Bonnycastle, Lori L | Hercberg, Serge | Dimitriou, Maria | Bolton, Jennifer L | Fowkes, Gerard R | Kovacs, Peter | Lindström, Jaana | Zemunik, Tatijana | Bandinelli, Stefania | Wild, Sarah H | Basart, Hanneke V | Rathmann, Wolfgang | Grallert, Harald | Maerz, Winfried | Kleber, Marcus E | Boehm, Bernhard O | Peters, Annette | Pramstaller, Peter P | Province, Michael A | Borecki, Ingrid B | Hastie, Nicholas D | Rudan, Igor | Campbell, Harry | Watkins, Hugh | Farrall, Martin | Stumvoll, Michael | Ferrucci, Luigi | Waterworth, Dawn M | Bergman, Richard N | Collins, Francis S | Tuomilehto, Jaakko | Watanabe, Richard M | de Geus, Eco J C | Penninx, Brenda W | Hofman, Albert | Oostra, Ben A | Psaty, Bruce M | Vollenweider, Peter | Wilson, James F | Wright, Alan F | Hovingh, G Kees | Metspalu, Andres | Uusitupa, Matti | Magnusson, Patrik K E | Kyvik, Kirsten O | Kaprio, Jaakko | Price, Jackie F | Dedoussis, George V | Deloukas, Panos | Meneton, Pierre | Lind, Lars | Boehnke, Michael | Shuldiner, Alan R | van Duijn, Cornelia M | Morris, Andrew D | Toenjes, Anke | Peyser, Patricia A | Beilby, John P | Körner, Antje | Kuusisto, Johanna | Laakso, Markku | Bornstein, Stefan R | Schwarz, Peter E H | Lakka, Timo A | Rauramaa, Rainer | Adair, Linda S | Smith, George Davey | Spector, Tim D | Illig, Thomas | de Faire, Ulf | Hamsten, Anders | Gudnason, Vilmundur | Kivimaki, Mika | Hingorani, Aroon | Keinanen-Kiukaanniemi, Sirkka M | Saaristo, Timo E | Boomsma, Dorret I | Stefansson, Kari | van der Harst, Pim | Dupuis, Josée | Pedersen, Nancy L | Sattar, Naveed | Harris, Tamara B | Cucca, Francesco | Ripatti, Samuli | Salomaa, Veikko | Mohlke, Karen L | Balkau, Beverley | Froguel, Philippe | Pouta, Anneli | Jarvelin, Marjo-Riitta | Wareham, Nicholas J | Bouatia-Naji, Nabila | McCarthy, Mark I | Franks, Paul W | Meigs, James B | Teslovich, Tanya M | Florez, Jose C | Langenberg, Claudia | Ingelsson, Erik | Prokopenko, Inga | Barroso, Inês
Nature genetics  2012;44(9):991-1005.
Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have raised the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional follow-up of these newly discovered loci will further improve our understanding of glycemic control.
doi:10.1038/ng.2385
PMCID: PMC3433394  PMID: 22885924
16.  Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes 
Morris, Andrew P | Voight, Benjamin F | Teslovich, Tanya M | Ferreira, Teresa | Segrè, Ayellet V | Steinthorsdottir, Valgerdur | Strawbridge, Rona J | Khan, Hassan | Grallert, Harald | Mahajan, Anubha | Prokopenko, Inga | Kang, Hyun Min | Dina, Christian | Esko, Tonu | Fraser, Ross M | Kanoni, Stavroula | Kumar, Ashish | Lagou, Vasiliki | Langenberg, Claudia | Luan, Jian'an | Lindgren, Cecilia M | Müller-Nurasyid, Martina | Pechlivanis, Sonali | Rayner, N William | Scott, Laura J | Wiltshire, Steven | Yengo, Loic | Kinnunen, Leena | Rossin, Elizabeth J | Raychaudhuri, Soumya | Johnson, Andrew D | Dimas, Antigone S | Loos, Ruth J F | Vedantam, Sailaja | Chen, Han | Florez, Jose C | Fox, Caroline | Liu, Ching-Ti | Rybin, Denis | Couper, David J | Kao, Wen Hong L | Li, Man | Cornelis, Marilyn C | Kraft, Peter | Sun, Qi | van Dam, Rob M | Stringham, Heather M | Chines, Peter S | Fischer, Krista | Fontanillas, Pierre | Holmen, Oddgeir L | Hunt, Sarah E | Jackson, Anne U | Kong, Augustine | Lawrence, Robert | Meyer, Julia | Perry, John RB | Platou, Carl GP | Potter, Simon | Rehnberg, Emil | Robertson, Neil | Sivapalaratnam, Suthesh | Stančáková, Alena | Stirrups, Kathleen | Thorleifsson, Gudmar | Tikkanen, Emmi | Wood, Andrew R | Almgren, Peter | Atalay, Mustafa | Benediktsson, Rafn | Bonnycastle, Lori L | Burtt, Noël | Carey, Jason | Charpentier, Guillaume | Crenshaw, Andrew T | Doney, Alex S F | Dorkhan, Mozhgan | Edkins, Sarah | Emilsson, Valur | Eury, Elodie | Forsen, Tom | Gertow, Karl | Gigante, Bruna | Grant, George B | Groves, Christopher J | Guiducci, Candace | Herder, Christian | Hreidarsson, Astradur B | Hui, Jennie | James, Alan | Jonsson, Anna | Rathmann, Wolfgang | Klopp, Norman | Kravic, Jasmina | Krjutškov, Kaarel | Langford, Cordelia | Leander, Karin | Lindholm, Eero | Lobbens, Stéphane | Männistö, Satu | Mirza, Ghazala | Mühleisen, Thomas W | Musk, Bill | Parkin, Melissa | Rallidis, Loukianos | Saramies, Jouko | Sennblad, Bengt | Shah, Sonia | Sigurðsson, Gunnar | Silveira, Angela | Steinbach, Gerald | Thorand, Barbara | Trakalo, Joseph | Veglia, Fabrizio | Wennauer, Roman | Winckler, Wendy | Zabaneh, Delilah | Campbell, Harry | van Duijn, Cornelia | Uitterlinden89-, Andre G | Hofman, Albert | Sijbrands, Eric | Abecasis, Goncalo R | Owen, Katharine R | Zeggini, Eleftheria | Trip, Mieke D | Forouhi, Nita G | Syvänen, Ann-Christine | Eriksson, Johan G | Peltonen, Leena | Nöthen, Markus M | Balkau, Beverley | Palmer, Colin N A | Lyssenko, Valeriya | Tuomi, Tiinamaija | Isomaa, Bo | Hunter, David J | Qi, Lu | Shuldiner, Alan R | Roden, Michael | Barroso, Ines | Wilsgaard, Tom | Beilby, John | Hovingh, Kees | Price, Jackie F | Wilson, James F | Rauramaa, Rainer | Lakka, Timo A | Lind, Lars | Dedoussis, George | Njølstad, Inger | Pedersen, Nancy L | Khaw, Kay-Tee | Wareham, Nicholas J | Keinanen-Kiukaanniemi, Sirkka M | Saaristo, Timo E | Korpi-Hyövälti, Eeva | Saltevo, Juha | Laakso, Markku | Kuusisto, Johanna | Metspalu, Andres | Collins, Francis S | Mohlke, Karen L | Bergman, Richard N | Tuomilehto, Jaakko | Boehm, Bernhard O | Gieger, Christian | Hveem, Kristian | Cauchi, Stephane | Froguel, Philippe | Baldassarre, Damiano | Tremoli, Elena | Humphries, Steve E | Saleheen, Danish | Danesh, John | Ingelsson, Erik | Ripatti, Samuli | Salomaa, Veikko | Erbel, Raimund | Jöckel, Karl-Heinz | Moebus, Susanne | Peters, Annette | Illig, Thomas | de Faire, Ulf | Hamsten, Anders | Morris, Andrew D | Donnelly, Peter J | Frayling, Timothy M | Hattersley, Andrew T | Boerwinkle, Eric | Melander, Olle | Kathiresan, Sekar | Nilsson, Peter M | Deloukas, Panos | Thorsteinsdottir, Unnur | Groop, Leif C | Stefansson, Kari | Hu, Frank | Pankow, James S | Dupuis, Josée | Meigs, James B | Altshuler, David | Boehnke, Michael | McCarthy, Mark I
Nature genetics  2012;44(9):981-990.
To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip involving 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two demonstrating sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of further common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signalling and cell cycle regulation, in diabetes pathogenesis.
doi:10.1038/ng.2383
PMCID: PMC3442244  PMID: 22885922
17.  Rate of de novo mutations, father’s age, and disease risk 
Nature  2012;488(7412):471-475.
Mutations generate sequence diversity and provide a substrate for selection. The rate of de novo mutations is therefore of major importance to evolution. We conducted a study of genomewide mutation rate by sequencing the entire genomes of 78 Icelandic parent-offspring trios at high coverage. Here we show that in our samples, with an average father’s age of 29.7, the average de novo mutation rate is 1.20×10−8 per nucleotide per generation. Most strikingly, the diversity in mutation rate of single-nucleotide polymorphism (SNP) is dominated by the age of the father at conception of the child. The effect is an increase of about 2 mutations per year. After accounting for random Poisson variation, father’s age is estimated to explain nearly all of the remaining variation in the de novo mutation counts. These observations shed light on the importance of the father’s age on the risk of diseases such as schizophrenia and autism.
doi:10.1038/nature11396
PMCID: PMC3548427  PMID: 22914163
18.  Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes 
Morris, Andrew P | Voight, Benjamin F | Teslovich, Tanya M | Ferreira, Teresa | Segré, Ayellet V | Steinthorsdottir, Valgerdur | Strawbridge, Rona J | Khan, Hassan | Grallert, Harald | Mahajan, Anubha | Prokopenko, Inga | Kang, Hyun Min | Dina, Christian | Esko, Tonu | Fraser, Ross M | Kanoni, Stavroula | Kumar, Ashish | Lagou, Vasiliki | Langenberg, Claudia | Luan, Jian’an | Lindgren, Cecilia M | Müller-Nurasyid, Martina | Pechlivanis, Sonali | Rayner, N William | Scott, Laura J | Wiltshire, Steven | Yengo, Loic | Kinnunen, Leena | Rossin, Elizabeth J | Raychaudhuri, Soumya | Johnson, Andrew D | Dimas, Antigone S | Loos, Ruth J F | Vedantam, Sailaja | Chen, Han | Florez, Jose C | Fox, Caroline | Liu, Ching-Ti | Rybin, Denis | Couper, David J | Kao, Wen Hong L | Li, Man | Cornelis, Marilyn C | Kraft, Peter | Sun, Qi | van Dam, Rob M | Stringham, Heather M | Chines, Peter S | Fischer, Krista | Fontanillas, Pierre | Holmen, Oddgeir L | Hunt, Sarah E | Jackson, Anne U | Kong, Augustine | Lawrence, Robert | Meyer, Julia | Perry, John R B | Platou, Carl G P | Potter, Simon | Rehnberg, Emil | Robertson, Neil | Sivapalaratnam, Suthesh | Stančáková, Alena | Stirrups, Kathleen | Thorleifsson, Gudmar | Tikkanen, Emmi | Wood, Andrew R | Almgren, Peter | Atalay, Mustafa | Benediktsson, Rafn | Bonnycastle, Lori L | Burtt, Noël | Carey, Jason | Charpentier, Guillaume | Crenshaw, Andrew T | Doney, Alex S F | Dorkhan, Mozhgan | Edkins, Sarah | Emilsson, Valur | Eury, Elodie | Forsen, Tom | Gertow, Karl | Gigante, Bruna | Grant, George B | Groves, Christopher J | Guiducci, Candace | Herder, Christian | Hreidarsson, Astradur B | Hui, Jennie | James, Alan | Jonsson, Anna | Rathmann, Wolfgang | Klopp, Norman | Kravic, Jasmina | Krjutškov, Kaarel | Langford, Cordelia | Leander, Karin | Lindholm, Eero | Lobbens, Stéphane | Männistö, Satu | Mirza, Ghazala | Mühleisen, Thomas W | Musk, Bill | Parkin, Melissa | Rallidis, Loukianos | Saramies, Jouko | Sennblad, Bengt | Shah, Sonia | Sigurðsson, Gunnar | Silveira, Angela | Steinbach, Gerald | Thorand, Barbara | Trakalo, Joseph | Veglia, Fabrizio | Wennauer, Roman | Winckler, Wendy | Zabaneh, Delilah | Campbell, Harry | van Duijn, Cornelia | Uitterlinden, Andre G | Hofman, Albert | Sijbrands, Eric | Abecasis, Goncalo R | Owen, Katharine R | Zeggini, Eleftheria | Trip, Mieke D | Forouhi, Nita G | Syvänen, Ann-Christine | Eriksson, Johan G | Peltonen, Leena | Nöthen, Markus M | Balkau, Beverley | Palmer, Colin N A | Lyssenko, Valeriya | Tuomi, Tiinamaija | Isomaa, Bo | Hunter, David J | Qi, Lu | Shuldiner, Alan R | Roden, Michael | Barroso, Ines | Wilsgaard, Tom | Beilby, John | Hovingh, Kees | Price, Jackie F | Wilson, James F | Rauramaa, Rainer | Lakka, Timo A | Lind, Lars | Dedoussis, George | Njølstad, Inger | Pedersen, Nancy L | Khaw, Kay-Tee | Wareham, Nicholas J | Keinanen-Kiukaanniemi, Sirkka M | Saaristo, Timo E | Korpi-Hyövälti, Eeva | Saltevo, Juha | Laakso, Markku | Kuusisto, Johanna | Metspalu, Andres | Collins, Francis S | Mohlke, Karen L | Bergman, Richard N | Tuomilehto, Jaakko | Boehm, Bernhard O | Gieger, Christian | Hveem, Kristian | Cauchi, Stephane | Froguel, Philippe | Baldassarre, Damiano | Tremoli, Elena | Humphries, Steve E | Saleheen, Danish | Danesh, John | Ingelsson, Erik | Ripatti, Samuli | Salomaa, Veikko | Erbel, Raimund | Jöckel, Karl-Heinz | Moebus, Susanne | Peters, Annette | Illig, Thomas | de Faire, Ulf | Hamsten, Anders | Morris, Andrew D | Donnelly, Peter J | Frayling, Timothy M | Hattersley, Andrew T | Boerwinkle, Eric | Melander, Olle | Kathiresan, Sekar | Nilsson, Peter M | Deloukas, Panos | Thorsteinsdottir, Unnur | Groop, Leif C | Stefansson, Kari | Hu, Frank | Pankow, James S | Dupuis, Josée | Meigs, James B | Altshuler, David | Boehnke, Michael | McCarthy, Mark I
Nature genetics  2012;44(9):981-990.
To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip involving 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two demonstrating sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of further common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signalling and cell cycle regulation, in diabetes pathogenesis.
doi:10.1038/ng.2383
PMCID: PMC3442244  PMID: 22885922
19.  Genetic correction of PSA values using sequence variants associated with PSA levels 
Science translational medicine  2010;2(62):62ra92.
Measuring serum levels of the prostate specific antigen (PSA) is the most common screening method for prostate cancer. However, PSA levels are affected by a number of factors apart from neoplasia. Notably, around 40% of the variability of PSA levels in the general population is accounted for by inherited factors, suggesting that it may be possible to improve both sensitivity and specificity by adjusting test results for genetic effects. In order to search for sequence variants that associate with PSA levels, we performed a genome-wide association study and follow-up analysis using PSA information from 15,757 Icelandic and 454 British men not diagnosed with prostate cancer. Overall, we detected a genome-wide significant association between PSA levels and SNPs at six loci: 5p15.33 (rs2736098), 10q11 (rs10993994), 10q26 (rs10788160), 12q24 (rs11067228), 17q12 (rs4430796), and 19q13.33 (rs17632542 (KLK3: I179T), each with Pcombined < 3×10−10. Among 3,834 men who underwent a biopsy of the prostate, the 10q26, 12q24, and 19q13.33 alleles that associate with high PSA levels are associated with higher probability of a negative biopsy (OR between 1.15 and 1.27). Assessment of association between the 6 loci and prostate cancer risk in 5,325 cases and 41,417 controls from Iceland, the Netherlands, Spain, Romania, and the US showed that the SNPs at 10q26 and 12q24 were exclusively associated with PSA levels, whereas the other 4 loci also were associated with prostate cancer risk. We propose that a personalized PSA cutoff value, based on genotype, should be used when deciding to perform a prostate biopsy.
doi:10.1126/scitranslmed.3001513
PMCID: PMC3564581  PMID: 21160077
20.  Genome-wide association and replication studies identify four variants associated with prostate cancer susceptibility 
Nature genetics  2009;41(10):1122-1126.
We report a genome-wide association follow up study on prostate cancer. We identify four variants associated with the disease in European populations: rs10934853-A (OR = 1.12, P = 2.9×10−10) on 3q21.3, two moderately correlated (r2 = 0.07) variants on 8q24.21; rs16902094-G (OR = 1.21, P = 6.2×10−15) and rs445114-T (OR = 1.14, P = 4.7×10−10) and rs8102476-C (OR = 1.12, P = 1.6×10−11) on 19q13.2. We also refine a previous association signal on 11q13 with the SNP rs11228565-A (OR =1.23, P = 6.7 × 10−12). In a multi-variant analysis, using 22 prostate cancer risk variants typed in the Icelandic population, we estimate that carriers belonging to the top 1.3% of the risk distribution have a risk of developing the disease that is more than 2.5 times greater than the population average risk estimates.
doi:10.1038/ng.448
PMCID: PMC3562712  PMID: 19767754
21.  Variants in MTNR1B influence fasting glucose levels 
Prokopenko, Inga | Langenberg, Claudia | Florez, Jose C | Saxena, Richa | Soranzo, Nicole | Thorleifsson, Gudmar | Loos, Ruth J F | Manning, Alisa K | Jackson, Anne U | Aulchenko, Yurii | Potter, Simon C | Erdos, Michael R | Sanna, Serena | Hottenga, Jouke-Jan | Wheeler, Eleanor | Kaakinen, Marika | Lyssenko, Valeriya | Chen, Wei-Min | Ahmadi, Kourosh | Beckmann, Jacques S | Bergman, Richard N | Bochud, Murielle | Bonnycastle, Lori L | Buchanan, Thomas A | Cao, Antonio | Cervino, Alessandra | Coin, Lachlan | Collins, Francis S | Crisponi, Laura | de Geus, Eco J C | Dehghan, Abbas | Deloukas, Panos | Doney, Alex S F | Elliott, Paul | Freimer, Nelson | Gateva, Vesela | Herder, Christian | Hofman, Albert | Hughes, Thomas E | Hunt, Sarah | Illig, Thomas | Inouye, Michael | Isomaa, Bo | Johnson, Toby | Kong, Augustine | Krestyaninova, Maria | Kuusisto, Johanna | Laakso, Markku | Lim, Noha | Lindblad, Ulf | Lindgren, Cecilia M | McCann, Owen T | Mohlke, Karen L | Morris, Andrew D | Naitza, Silvia | Orrù, Marco | Palmer, Colin N A | Pouta, Anneli | Randall, Joshua | Rathmann, Wolfgang | Saramies, Jouko | Scheet, Paul | Scott, Laura J | Scuteri, Angelo | Sharp, Stephen | Sijbrands, Eric | Smit, Jan H | Song, Kijoung | Steinthorsdottir, Valgerdur | Stringham, Heather M | Tuomi, Tiinamaija | Tuomilehto, Jaakko | Uitterlinden, André G | Voight, Benjamin F | Waterworth, Dawn | Wichmann, H-Erich | Willemsen, Gonneke | Witteman, Jacqueline C M | Yuan, Xin | Zhao, Jing Hua | Zeggini, Eleftheria | Schlessinger, David | Sandhu, Manjinder | Boomsma, Dorret I | Uda, Manuela | Spector, Tim D | Penninx, Brenda WJH | Altshuler, David | Vollenweider, Peter | Jarvelin, Marjo Riitta | Lakatta, Edward | Waeber, Gerard | Fox, Caroline S | Peltonen, Leena | Groop, Leif C | Mooser, Vincent | Cupples, L Adrienne | Thorsteinsdottir, Unnur | Boehnke, Michael | Barroso, Inês | Van Duijn, Cornelia | Dupuis, Josée | Watanabe, Richard M | Stefansson, Kari | McCarthy, Mark I | Wareham, Nicholas J | Meigs, James B | Abecasis, Gonçalo R
Nature genetics  2008;41(1):77-81.
To identify previously unknown genetic loci associated with fasting glucose concentrations, we examined the leading association signals in ten genome-wide association scans involving a total of 36,610 individuals of European descent. Variants in the gene encoding melatonin receptor 1B (MTNR1B) were consistently associated with fasting glucose across all ten studies. The strongest signal was observed at rs10830963, where each G allele (frequency 0.30 in HapMap CEU) was associated with an increase of 0.07 (95% CI = 0.06-0.08) mmol/l in fasting glucose levels (P = 3.2 = × 10−50) and reduced beta-cell function as measured by homeostasis model assessment (HOMA-B, P = 1.1 × 10−15). The same allele was associated with an increased risk of type 2 diabetes (odds ratio = 1.09 (1.05-1.12), per G allele P = 3.3 × 10−7) in a meta-analysis of 13 case-control studies totaling 18,236 cases and 64,453 controls. Our analyses also confirm previous associations of fasting glucose with variants at the G6PC2 (rs560887, P = 1.1 × 10−57) and GCK (rs4607517, P = 1.0 × 10−25) loci.
doi:10.1038/ng.290
PMCID: PMC2682768  PMID: 19060907
22.  European genome-wide association study identifies SLC14A1 as a new urinary bladder cancer susceptibility gene 
Rafnar, Thorunn | Vermeulen, Sita H. | Sulem, Patrick | Thorleifsson, Gudmar | Aben, Katja K. | Witjes, J. Alfred | Grotenhuis, Anne J. | Verhaegh, Gerald W. | Hulsbergen-van de Kaa, Christina A. | Besenbacher, Soren | Gudbjartsson, Daniel | Stacey, Simon N. | Gudmundsson, Julius | Johannsdottir, Hrefna | Bjarnason, Hjordis | Zanon, Carlo | Helgadottir, Hafdis | Jonasson, Jon Gunnlaugur | Tryggvadottir, Laufey | Jonsson, Eirikur | Geirsson, Gudmundur | Nikulasson, Sigfus | Petursdottir, Vigdis | Bishop, D. Timothy | Chung-Sak, Sei | Choudhury, Ananya | Elliott, Faye | Barrett, Jennifer H. | Knowles, Margaret A. | de Verdier, Petra J. | Ryk, Charlotta | Lindblom, Annika | Rudnai, Peter | Gurzau, Eugene | Koppova, Kvetoslava | Vineis, Paolo | Polidoro, Silvia | Guarrera, Simonetta | Sacerdote, Carlotta | Panadero, Angeles | Sanz-Velez, José I. | Sanchez, Manuel | Valdivia, Gabriel | Garcia-Prats, Maria D. | Hengstler, Jan G. | Selinski, Silvia | Gerullis, Holger | Ovsiannikov, Daniel | Khezri, Abdolaziz | Aminsharifi, Alireza | Malekzadeh, Mahyar | van den Berg, Leonard H. | Ophoff, Roel A. | Veldink, Jan H. | Zeegers, Maurice P. | Kellen, Eliane | Fostinelli, Jacopo | Andreoli, Daniele | Arici, Cecilia | Porru, Stefano | Buntinx, Frank | Ghaderi, Abbas | Golka, Klaus | Mayordomo, José I. | Matullo, Giuseppe | Kumar, Rajiv | Steineck, Gunnar | Kiltie, Anne E. | Kong, Augustine | Thorsteinsdottir, Unnur | Stefansson, Kari | Kiemeney, Lambertus A.
Human Molecular Genetics  2011;20(21):4268-4281.
Three genome-wide association studies in Europe and the USA have reported eight urinary bladder cancer (UBC) susceptibility loci. Using extended case and control series and 1000 Genomes imputations of 5 340 737 single-nucleotide polymorphisms (SNPs), we searched for additional loci in the European GWAS. The discovery sample set consisted of 1631 cases and 3822 controls from the Netherlands and 603 cases and 37 781 controls from Iceland. For follow-up, we used 3790 cases and 7507 controls from 13 sample sets of European and Iranian ancestry. Based on the discovery analysis, we followed up signals in the urea transporter (UT) gene SLC14A. The strongest signal at this locus was represented by a SNP in intron 3, rs17674580, that reached genome-wide significance in the overall analysis of the discovery and follow-up groups: odds ratio = 1.17, P = 7.6 × 10−11. SLC14A1 codes for UTs that define the Kidd blood group and are crucial for the maintenance of a constant urea concentration gradient in the renal medulla and, through this, the kidney's ability to concentrate urine. It is speculated that rs17674580, or other sequence variants in LD with it, indirectly modifies UBC risk by affecting urine production. If confirmed, this would support the ‘urogenous contact hypothesis’ that urine production and voiding frequency modify the risk of UBC.
doi:10.1093/hmg/ddr303
PMCID: PMC3188988  PMID: 21750109
23.  A germline variant in the TP53 polyadenylation signal confers cancer susceptibility 
Stacey, Simon N | Sulem, Patrick | Jonasdottir, Aslaug | Masson, Gisli | Gudmundsson, Julius | Gudbjartsson, Daniel F | Magnusson, Olafur T | Gudjonsson, Sigurjon A | Sigurgeirsson, Bardur | Thorisdottir, Kristin | Ragnarsson, Rafn | Benediktsdottir, Kristrun R | Nexø, Bjørn A | Tjønneland, Anne | Overvad, Kim | Rudnai, Peter | Gurzau, Eugene | Koppova, Kvetoslava | Hemminki, Kari | Corredera, Cristina | Fuentelsaz, Victoria | Grasa, Pilar | Navarrete, Sebastian | Fuertes, Fernando | García-Prats, Maria D | Sanambrosio, Enrique | Panadero, Angeles | De Juan, Ana | Garcia, Almudena | Rivera, Fernando | Planelles, Dolores | Soriano, Virtudes | Requena, Celia | Aben, Katja K | van Rossum, Michelle M | Cremers, Ruben G H M | van Oort, Inge M | van Spronsen, Dick-Johan | Schalken, Jack A | Peters, Wilbert H M | Helfand, Brian T | Donovan, Jenny L | Hamdy, Freddie C | Badescu, Daniel | Codreanu, Ovidiu | Jinga, Mariana | Csiki, Irma E | Constantinescu, Vali | Badea, Paula | Mates, Ioan N | Dinu, Daniela E | Constantin, Adrian | Mates, Dana | Kristjansdottir, Sjofn | Agnarsson, Bjarni A | Jonsson, Eirikur | Barkardottir, Rosa B | Einarsson, Gudmundur V | Sigurdsson, Fridbjorn | Moller, Pall H | Stefansson, Tryggvi | Valdimarsson, Trausti | Johannsson, Oskar T | Sigurdsson, Helgi | Jonsson, Thorvaldur | Jonasson, Jon G | Tryggvadottir, Laufey | Rice, Terri | Hansen, Helen M | Xiao, Yuanyuan | Lachance, Daniel H | O’Neill, Brian Patrick | Kosel, Matthew L | Decker, Paul A | Thorleifsson, Gudmar | Johannsdottir, Hrefna | Helgadottir, Hafdis T | Sigurdsson, Asgeir | Steinthorsdottir, Valgerdur | Lindblom, Annika | Sandler, Robert S | Keku, Temitope O | Banasik, Karina | Jørgensen, Torben | Witte, Daniel R | Hansen, Torben | Pedersen, Oluf | Jinga, Viorel | Neal, David E | Catalona, William J | Wrensch, Margaret | Wiencke, John | Jenkins, Robert B | Nagore, Eduardo | Vogel, Ulla | Kiemeney, Lambertus A | Kumar, Rajiv | Mayordomo, José I | Olafsson, Jon H | Kong, Augustine | Thorsteinsdottir, Unnur | Rafnar, Thorunn | Stefansson, Kari
Nature Genetics  2011;43(11):1098-1103.
To identify new risk variants for cutaneous basal cell carcinoma, we performed a genome-wide association study of 16 million SNPs identified through whole-genome sequencing of 457 Icelanders. We imputed genotypes for 41,675 Illumina SNP chip-typed Icelanders and their relatives. In the discovery phase, the strongest signal came from rs78378222[C] (odds ratio (OR) = 2.36, P = 5.2 × 10−17), which has a frequency of 0.0192 in the Icelandic population. We then confirmed this association in non-Icelandic samples (OR = 1.75, P = 0.0060; overall OR = 2.16, P = 2.2 × 10−20). rs78378222 is in the 3′ untranslated region of TP53 and changes the AATAAA polyadenylation signal to AATACA, resulting in impaired 3′-end processing of TP53 mRNA. Investigation of other tumor types identified associations of this SNP with prostate cancer (OR = 1.44, P = 2.4 × 10−6), glioma (OR = 2.35, P = 1.0 × 10−5) and colorectal adenoma (OR = 1.39, P = 1.6 × 10−4). However, we observed no effect for breast cancer, a common Li-Fraumeni syndrome tumor (OR = 1.06, P = 0.57, 95% confidence interval 0.88–1.27).
doi:10.1038/ng.926
PMCID: PMC3263694  PMID: 21946351
24.  Common variants at VRK2 and TCF4 conferring risk of schizophrenia 
Steinberg, Stacy | de Jong, Simone | Andreassen, Ole A. | Werge, Thomas | Børglum, Anders D. | Mors, Ole | Mortensen, Preben B. | Gustafsson, Omar | Costas, Javier | Pietiläinen, Olli P. H. | Demontis, Ditte | Papiol, Sergi | Huttenlocher, Johanna | Mattheisen, Manuel | Breuer, René | Vassos, Evangelos | Giegling, Ina | Fraser, Gillian | Walker, Nicholas | Tuulio-Henriksson, Annamari | Suvisaari, Jaana | Lönnqvist, Jouko | Paunio, Tiina | Agartz, Ingrid | Melle, Ingrid | Djurovic, Srdjan | Strengman, Eric | Jürgens, Gesche | Glenthøj, Birte | Terenius, Lars | Hougaard, David M. | Ørntoft, Torben | Wiuf, Carsten | Didriksen, Michael | Hollegaard, Mads V. | Nordentoft, Merete | van Winkel, Ruud | Kenis, Gunter | Abramova, Lilia | Kaleda, Vasily | Arrojo, Manuel | Sanjuán, Julio | Arango, Celso | Sperling, Swetlana | Rossner, Moritz | Ribolsi, Michele | Magni, Valentina | Siracusano, Alberto | Christiansen, Claus | Kiemeney, Lambertus A. | Veldink, Jan | van den Berg, Leonard | Ingason, Andres | Muglia, Pierandrea | Murray, Robin | Nöthen, Markus M. | Sigurdsson, Engilbert | Petursson, Hannes | Thorsteinsdottir, Unnur | Kong, Augustine | Rubino, I. Alex | De Hert, Marc | Réthelyi, János M. | Bitter, István | Jönsson, Erik G. | Golimbet, Vera | Carracedo, Angel | Ehrenreich, Hannelore | Craddock, Nick | Owen, Michael J. | O'Donovan, Michael C. | Ruggeri, Mirella | Tosato, Sarah | Peltonen, Leena | Ophoff, Roel A. | Collier, David A. | St Clair, David | Rietschel, Marcella | Cichon, Sven | Stefansson, Hreinn | Rujescu, Dan | Stefansson, Kari
Human Molecular Genetics  2011;20(20):4076-4081.
Common sequence variants have recently joined rare structural polymorphisms as genetic factors with strong evidence for association with schizophrenia. Here we extend our previous genome-wide association study and meta-analysis (totalling 7 946 cases and 19 036 controls) by examining an expanded set of variants using an enlarged follow-up sample (up to 10 260 cases and 23 500 controls). In addition to previously reported alleles in the major histocompatibility complex region, near neurogranin (NRGN) and in an intron of transcription factor 4 (TCF4), we find two novel variants showing genome-wide significant association: rs2312147[C], upstream of vaccinia-related kinase 2 (VRK2) [odds ratio (OR) = 1.09, P = 1.9 × 10−9] and rs4309482[A], between coiled-coiled domain containing 68 (CCDC68) and TCF4, about 400 kb from the previously described risk allele, but not accounted for by its association (OR = 1.09, P = 7.8 × 10−9).
doi:10.1093/hmg/ddr325
PMCID: PMC3298077  PMID: 21791550
25.  Sequence variants at CYP1A1–CYP1A2 and AHR associate with coffee consumption 
Human Molecular Genetics  2011;20(10):2071-2077.
Coffee is the most commonly used stimulant and caffeine is its main psychoactive ingredient. The heritability of coffee consumption has been estimated at around 50%. We performed a meta-analysis of four genome-wide association studies of coffee consumption among coffee drinkers from Iceland (n = 2680), the Netherlands (n = 2791), the Sorbs Slavonic population isolate in Germany (n = 771) and the USA (n = 369) using both directly genotyped and imputed single nucleotide polymorphisms (SNPs) (2.5 million SNPs). SNPs at the two most significant loci were also genotyped in a sample set from Iceland (n = 2430) and a Danish sample set consisting of pregnant women (n = 1620). Combining all data, two sequence variants significantly associated with increased coffee consumption: rs2472297-T located between CYP1A1 and CYP1A2 at 15q24 (P = 5.4 · 10−14) and rs6968865-T near aryl hydrocarbon receptor (AHR) at 7p21 (P = 2.3 · 10−11). An effect of ∼0.2 cups a day per allele was observed for both SNPs. CYP1A2 is the main caffeine metabolizing enzyme and is also involved in drug metabolism. AHR detects xenobiotics, such as polycyclic aryl hydrocarbons found in roasted coffee, and induces transcription of CYP1A1 and CYP1A2. The association of these SNPs with coffee consumption was present in both smokers and non-smokers.
doi:10.1093/hmg/ddr086
PMCID: PMC3080612  PMID: 21357676

Results 1-25 (59)