Research articles

Andrew Hattersley, Jorge Ferrer and colleagues use epigenomic annotation of pancreatic progenitor cells to guide the interpretation of whole-genome sequences from individuals with isolated pancreatic agenesis. They show that recessive mutations in a distal developmental enhancer of PTF1A cause pancreatic agenesis and abolish enhancer activity.

Xuejun Zhang, Jun Wang and colleagues report the application of exome sequencing to a large collection of psoriasis cases and controls. They identify seven common and low-frequency nonsynonymous variants within known psoriasis susceptibility genes that are associated with psoriasis risk.

Matthew Meyerson and colleagues report whole-exome and whole-genome sequencing of 55 small intestine neuroendocrine tumors. They identify recurrent somatic mutations in CDKN1B, implicating cell cycle dysregulation in the pathogenesis of these tumors.

Laura Wood, Kenneth Kinzler, Nickolas Papadopoulos, Aldo Scarpa and colleagues report exome sequencing of intrahepatic cholangiocarcinomas. They identify recurrent somatic mutations in BAP1, ARID1A and PBRM1.

Arul Chinnaiyan and colleagues report the results of prospective clinical sequencing of 11 estrogen receptor–positive metastatic breast cancers. They identify ESR1 mutations affecting the ligand-binding domain in six hormone-resistant metastatic breast cancers and show that the mutant estrogen receptors are constitutively active and continue to be responsive to anti-estrogen therapies in vitro.

Bin Tean Teh, Patrick Tan, Steven Rozen, Irinel Popescu and colleagues report exome sequencing of cholangiocarcinomas, including cases caused by liver fluke (Opisthorchis viverrini) infection and cases caused by non–O. viverrini etiologies. They identify recurrent somatic mutations in BAP1 and ARID1A and demonstrate different mutation patterns in liver fluke infection–related and non-infection-related cancers.

Sarat Chandarlapaty and colleagues report the identification of mutations in the ESR1 gene affecting the ligand-binding domain of the encoded estrogen receptor in 20% of metastatic hormone-resistant breast cancers. They determine that the mutant receptor has a hormone-independent active state that likely promotes resistance to estrogen-depriving therapies.

Adrienne Flanagan and colleagues identify distinct driver mutations in H3F3A and H3F3B in chondroblastoma and giant cell tumor of bone. The mutations occur in over 90% of tumors and exhibit a high degree of tumor type specificity.

Guo-Liang Xu, Duanqing Pei and colleagues show that during induced pluripotent cell reprogramming Tet1 regulates 5-hydroxymethylcytosine levels at loci critical for mesenchymal-to-epithelial transition in a vitamin C–dependent fashion. They also show that Tet1 either enhances or inhibits somatic cell reprogramming, depending on the absence or presence of vitamin C, respectively.

Ruiqiang Li and colleagues report the whole-genome sequencing of a Tibetan female wild boar, as well as resequencing of 48 domestic pigs and wild boar from Tibet and China. Their analysis provides insights into the genetic diversity, population structure and evolution of the wild boar.

Hongbing Shen and colleagues report a genome-wide association study for chronic hepatitis B virus (HBV) infection in Han Chinese populations. They identify two loci newly associated with HBV infection near HLA-C and UBLE2L3 and replicate previous associations at HLA-DP and HLA-DQ.

Philippe Amouyel, Julie Williams, Gerard Schellenberg, Sudha Seshadri and colleagues report a meta-analysis of genome-wide association studies for late-onset Alzheimer's disease in 17,008 cases and 37,154 controls with replication in an additional 8,572 cases and 11,312 controls. They identify 11 loci newly associated with Alzheimer's disease.

Sanwen Huang and colleagues report a genomic variation map of cucumber. They report the resequencing of 115 cucumber accessions and de novo assembly of the wild cucumber genome.

Jun Yang and colleagues show that common variants in GATA3 are associated with risk of Ph-like acute lymphoblastic leukemia (ALL). They further show that these variants are associated with variation in GATA3 expression levels and with risk of ALL relapse.

David Altshuler and colleagues explore the genetic architecture of type 2 diabetes (T2D) using an integrated population genetics–based simulation framework calibrated with empirical data. Whereas they are able to exclude more extreme models, for example, those in which either common or rare variants explain all of the disease heritability, they find that a broad range of architecture remains consistent with current empirical data and suggest that continued large-scale sequencing and genotyping studies will be needed to more precisely characterize the genetic architecture of complex traits such as T2D.

Todd Waldman and colleagues screened 2,214 tumors for loss of STAG2 expression using immunohistochemistry. They followed up by sequencing STAG2 in 111 urothelial carcinomas and found mutations in 23 of the cases, identifying STAG2 as one of the most commonly mutated genes in bladder cancer.

Thomas Vaughan and colleagues report a genome-wide association study of esophageal adenocarcinoma together with its precancerous lesion, Barrett's esophagus. They identified three loci associated with susceptibility to this cancer.

Zhiming Cai and colleagues report whole-genome and whole-exome sequencing of 99 paired tumor-normal samples of transitional cell carcinoma of the bladder. They find that 32% of tumors harbor alterations in genes involved in sister chromatid cohesion, including STAG2, ESPL1, NIPBL, SMC1A and SMC3.

Francisco Real and colleagues report exome sequencing in urothelial bladder tumors. They show that STAG2, a subunit of the cohesin complex, is recurrently mutated and provide evidence that STAG2 loss does not lead to increases in aneuploidy.

Kathy Sivils and colleagues report results of a large-scale association study of Sjögren's syndrome, a common autoimmune disease. They confirm strong associations with the HLA region and establish genome-wide significant associations at several non-HLA loci implicated in both innate and adaptive immunity.