Laufey Amundadottir

• Division of Cancer Epidemiology and Genetics, National Institutes of Health

Pancreatic Ductal Adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths in the U.S. Both rare and common germline variants contribute to PDAC risk. Here, we fine-map and functionally characterize a common PDAC risk signal at chr1p36.33 (tagged by rs13303010) identified through a genome wide association study (GWAS). One of the f...

Background Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths in the U.S. mainly because of late-stage diagnosis. Heritable genetic information can improve risk stratification for individuals with moderate to high-risk of PDAC for targeted screening and early detection. We aimed to develop an enhanced polyge...

Pancreatic ductal adenocarcinoma (PDAC) is predicted to become the second leading cause of cancer-related deaths by the end of this decade. There is an urgent need to improve risk stratification for prevention and diagnosis and identify novel targets for therapeutic intervention. Both epidemiological factors and genetic variants influence PDAC risk...

Objective The associations between different types of diabetes, characterized by distinct pathophysiology and genetic architecture, and pancreatic ductal adenocarcinoma (PDAC) risk are not fully understood. We investigated associations of genetic susceptibility to type 2 diabetes (T2D), its eight mechanistic clusters and type 1 diabetes (T1D) using...

Background Genome-wide association studies have identified an exon 6 CTRB2 deletion variant proposed to increase pancreatic cancer risk. Objective To acquire evidence on its causal role, we developed and analysed a new mouse strain carrying an equivalent variant in Ctrb1 , the mouse CTRB2 orthologue. Design We used CRISPR/Cas9 to introduce a 707...

770 Background: Pancreatic ductal adenocarcinoma (PDAC) is associated with poor prognosis and limited treatment options. A 584 bp deletion in CTRB2 , which impairs chymotrypsin B2 function, has been linked to increased PDAC risk. This study investigates the impact of this deletion on progression and survival outcomes in patients with PDAC. Methods:...

This important study presents genome-wide high-resolution chromatin-based 3D genomic interaction maps for over 50 diverse human cell types and integrates these data with pediatric obesity GWAS. The work provides convincing evidence that multiple pancreatic islet cell types are key effector cell types. The authors also perform variant-to-gene mappin...

The prevalence of childhood obesity is increasing worldwide, along with the associated common comorbidities of type 2 diabetes and cardiovascular disease in later life. Motivated by evidence for a strong genetic component, our prior genome-wide association study (GWAS) efforts for childhood obesity revealed 19 independent signals for the trait; how...

Pancreatic Ductal Adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths in the U.S. Both rare and common germline variants contribute to PDAC risk. Here, we fine-map and functionally characterize a common PDAC risk signal at 1p36.33 (tagged by rs13303010) identified through a genome wide association study (GWAS). One of the fine...

Genome-wide association studies (GWAS) have identified independent signals at 5p15.33 across numerous cancers, with protective alleles for one cancer often conferring risk for another. Many of these associations are thought to act via allele-specific alterations in the cis- regulation of target genes. Transcriptomic analyses in multiple tissue type...

Common low effect size germline variants are known to contribute to pancreatic ductal adenocarcinoma (PDAC) susceptibility. Genome-wide association studies (GWAS) for PDAC have identified over 20 loci where common germline variants influence PDAC risk. Understanding the underlying mechanisms of risk could improve detection, prevention, and potentia...

Genetic or epigenetic variations in regulatory enhancer elements increase susceptibility to a range of pathologies, including pancreas cancer. Pinpointing genes affecting pancreas cancer risk holds promise for early detection, prevention, and effective therapies. Despite recent advances, linking enhancer elements to target genes and predicting the...

Background: Genome-wide association studies (GWAS) have linked single nucleotide polymorphisms (SNPs) to pancreatic ductal adenocarcinoma (PDAC) risk at over 20 genomic loci. The Pancreatic Cancer Cohort Consortium and Pancreatic Cancer Case-Control Consortium are currently expanding on previous GWAS studies for PDAC from ∼9,000 cases and ∼12,000 c...

Genetic and epigenetic variations in regulatory enhancer elements increase susceptibility to a range of pathologies. Despite recent advances, linking enhancer elements to target genes and predicting transcriptional outcomes of enhancer dysfunction remain significant challenges. Using 3D chromatin conformation assays, we generated an extensive enhan...

A portion of the genetic basis for many common autoimmune disorders has been uncovered by genome-wide association studies (GWAS), but GWAS do not reveal causal variants, effector genes, or the cell types impacted by disease-associated variation. We have generated 3D genomic datasets consisting of promoter-focused Capture-C, Hi-C, ATAC-seq, and RNA-...

Recent genome-wide association studies (GWAS) have revealed shared genetic components among alcohol, opioid, tobacco and cannabis use disorders. However, the extent of the underlying shared causal variants and effector genes, along with their cellular context, remain unclear. We leveraged our existing 3D genomic datasets comprising high-resolution...

Background Pancreatic cancer is a leading cause of cancer-related death globally. Risk factors for pancreatic cancer include common genetic variants and potentially heavy alcohol consumption. We assessed if genetic variants modify the association between heavy alcohol consumption and pancreatic cancer risk. Methods We conducted a genome-wide inter...

Background: There are conflicting data on whether nonalcoholic fatty liver disease (NAFLD) is associated with susceptibility to pancreatic cancer (PC). Using Mendelian randomization (MR), we investigated the relationship between genetic predisposition to NAFLD and risk for PC. Methods: Data from genome-wide association studies within the Pancrea...

Background: In western populations, Pancreatic Ductal Adenocarcinoma (PDAC) risk has been found to be greater among individuals with non-O blood types than those with O blood type. However, the association has not been fully evaluated with respect to FUT2 (determining secretor status) and FUT3 (determining Lewis antigens) status, two biologically...

Here, we present a protocol to identify transcriptional regulators potentially mediating downstream biological effects of germline variants associated with complex traits of interest, which enables functional hypothesis generation independent of colocalizing expression quantitative trait loci (eQTLs). We describe steps for tissue-/cell-type-specifi...

Background Mendelian randomization (MR) studies are susceptible to metadata errors (e.g. incorrect specification of the effect allele column) and other analytical issues that can introduce substantial bias into analyses. We developed a quality control (QC) pipeline for the Fatty Acids in Cancer Mendelian Randomization Collaboration (FAMRC) that can...

The Integrated Physiology of the Exocrine and Endocrine Compartments in Pancreatic Diseases workshop was a 1.5-day scientific conference at the National Institutes of Health (Bethesda, MD) that engaged clinical and basic science investigators interested in diseases of the pancreas. This report provides a summary of the proceedings from the workshop...

Background: The shared inherited genetic contribution to risk of different cancers is not fully known. In this study, we leverage results from twelve cancer genome-wide association studies (GWAS) to quantify pair-wise genome-wide genetic correlations across cancers and identify novel cancer susceptibility loci. Methods: We collected GWAS summary...

The "Integrated Physiology of the Exocrine and Endocrine Compartments in Pancreatic Diseases" Workshop was a 1.5-day scientific conference at the National Institutes of Health (Bethesda, MD) that engaged clinical and basic science investigators interested in diseases of the pancreas. This report summarizes the workshop proceedings. The goal of the...

In western nations, pancreatic ductal adenocarcinoma (PDAC) is set to become second leading cause of cancer mortality over the next decade. Despite advances in treatment, PDAC has a 5-year survival rate of only ~9%, necessitating a better understanding of its etiology. Risk factors for PDAC are both environmental and genetic, with heritability esti...

Importance: Pancreatic cancer presents as advanced disease in >80% of patients; yet, appropriate ages to consider prevention and early detection strategies are poorly defined. Objective: To investigate age-specific associations and attributable risks of pancreatic cancer for established modifiable and non-modifiable risk factors. Design, Setting, a...

Background Pancreatic cancer presents as advanced disease in >80% of patients; yet, appropriate ages to consider prevention and early detection strategies are poorly defined. We investigated age-specific associations and attributable risks of pancreatic cancer for established modifiable and non-modifiable risk factors. Patients and methods We incl...

Expression QTL (eQTL) analyses have suggested many genes mediating genome-wide association study (GWAS) signals but most GWAS signals still lack compelling explanatory genes. We have leveraged an adipose-specific gene regulatory network to infer expression regulator activities and phenotypic master regulators (MRs), which were used to detect activi...

Genome-wide association studies (GWASs) have discovered 20 risk loci in the human genome where germline variants associate with risk of pancreatic ductal adenocarcinoma (PDAC) in populations of European ancestry. Here, we fine-mapped one such locus on chr16q23.1 (rs72802365, p = 2.51 × 10⁻¹⁷, OR = 1.36, 95% CI = 1.31–1.40) and identified colocaliza...

Background Epidemiological studies have suggested positive associations for iron and red meat intake with risk of pancreatic ductal adenocarcinoma (PDAC). Inherited pathogenic variants in genes involved in the hepcidin-regulating iron metabolism pathway are known to cause iron overload and hemochromatosis. Objectives The objective of this study wa...

Genome-wide association studies (GWAS) have identified thousands of cancer risk loci revealing many risk regions shared across multiple cancers. Characterizing the cross-cancer shared genetic basis can increase our understanding of global mechanisms of cancer development. In this study, we collected GWAS summary statistics based on up to 375,468 ca...

Germline variation and smoking are independently associated with pancreatic ductal adenocarcinoma (PDAC). We conducted genome-wide smoking interaction analysis of PDAC using genotype data from four previous genome-wide association studies in individuals of European ancestry (7,937 cases and 11,774 controls). Examination of expression quantitative t...

Jews are estimated to be at increased risk of pancreatic cancer compared to non-Jews, but their observed 50–80% excess risk is not explained by known non-genetic or genetic risk factors. We conducted a GWAS in a case–control sample of American Jews, largely Ashkenazi, including 406 pancreatic cancer patients and 2332 controls, identified in the dbG...

Background Pancreatic cancer (PC) is a complex disease in which both non-genetic and genetic factors interplay. To date, 40 GWAS hits have been associated with PC risk in individuals of European descent, explaining 4.1% of the phenotypic variance. Methods We complemented a new conventional PC GWAS (1D) with genome spatial autocorrelation analysis...

Genome wide association studies (GWAS) in 9,013 pancreatic cancer patients and 12,452 controls of European ancestry have discovered over 20 risk loci in the human genome. Here, we fine mapped one such locus on chromosome 16q23.1 in the vicinity of two Chymotrypsinogen precursor genes, CTRB1 and CTRB2. We fine-mapped this locus to rs72802365 (P=2.51...

Background: Whether circulating polyunsaturated fatty acids (PUFA) levels are associated with pancreatic cancer risk is uncertain. Mendelian randomization (MR) represents a study design using genetic instruments to better characterize the relationship between exposure and outcome. Methods: We utilized data from genome-wide association studies wi...

Pancreatic ductal adenocarcinoma (PDAC) is one of most lethal malignancies with few known risk factors and biomarkers. Identification of disease biomarkers is critical for understanding the pathogenesis of this cancer and identifying high risk individuals for close surveillance. Several blood protein biomarkers have been linked to PDAC in previous...

Introduction: Pancreatic cancer is the seventh leading cause of cancer death worldwide with pancreatic ductal adenocarcinoma (PDAC) being the most common subtype (>90%). Inherited genetic changes and cigarette smoking are established independent risk factors of PDAC. Methods: We conducted a genome-wide gene by smoking interaction analysis of PDAC r...

Genome-wide association studies (GWAS) have identified hundreds of common, low-penetrance alleles associated with cancer risk. However, known rare and common risk alleles only explain between 10% and 30% of the familial relative risk for different cancers and multiple lines of evidence indicate that many more risk alleles remain to be discovered. W...

Registry-based epidemiologic studies suggest associations between chronic inflammatory intestinal diseases and pancreatic ductal adenocarcinoma (PDAC). As genetic susceptibility contributes to a large proportion of chronic inflammatory intestinal diseases, we hypothesize that the genomic regions surrounding established genome-wide associated varian...

Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and under...

Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and under...

Pancreatic cancer is the fourth leading cause of cancer-related deaths in Japan. To identify risk loci, we perform a meta-analysis of three genome-wide association studies comprising 2,039 pancreatic cancer patients and 32,592 controls in the Japanese population. Here, we identify 3 (13q12.2, 13q22.1, and 16p12.3) genome-wide significant loci (P <...

Background: Obesity and diabetes are major modifiable risk factors for pancreatic cancer. Interactions between genetic variants and diabetes/obesity have not previously been comprehensively investigated in pancreatic cancer at the genome-wide level. Methods: We conducted a gene-environment interaction (GxE) analysis including 8,255 cases and 11,...

Background: Pancreatic cancer is the third leading cause of cancer death in the United States, and 80% of patients present with advanced, incurable disease. Risk markers for pancreatic cancer have been characterized, but combined models are not used clinically to identify individuals at high risk for the disease. Methods: Within a nested case-co...

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer, and epidemiological studies have suggested positive associations with iron and red meat intake. Rare mutations in genes involved in the hepcidin-regulating pathway are known to cause iron overload and hemochromatosis. We hypothesize that the hepcidin-regulating pathway as characteri...

Pancreatic cancer (PC) is a complex disease in which both non-genetic and genetic factors interplay. To-date, 40 GWAS hits have been associated with PC risk in individuals of European descent, explaining 4.1% of the phenotypic variance. Here, we complemented a classical new PC GWAS (1D) with spatial autocorrelation analysis (2D) and Hi-C maps (3D)...

Background: Although 20 pancreatic cancer susceptibility loci have been identified through genome-wide association studies (GWAS) in individuals of European ancestry, much of its heritability remains unexplained and the genes responsible largely unknown. Methods: To discover novel pancreatic cancer risk loci and possible causal genes, we perform...

Background: Leukocyte telomere length has been associated with risk of subsequent pancreatic cancer. Few prospective studies have evaluated the association of prediagnostic leukocyte telomere length with pancreatic cancer survival. Methods: We prospectively examined the association of prediagnostic leukocyte telomere length with overall survival...

We analyzed summary-level data from genome-wide association studies (GWAS) of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) contributing to risk, as well as the distribution of their associated effect sizes. All cancers evaluated showed polygenicity, involving at a minimum tho...

Pancreatic Ductal Adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths in United States with a 5-year survival rate of only 8%. Inherited predisposition plays an important role in PDAC risk. Rare, moderately to highly penetrant mutations in hereditary cancer and pancreatitis genes, identified in families with a high incidence o...

Objective: The KRAS gene is the most frequently mutated gene in pancreatic cancer, and no successful anti-Ras therapy has been developed. Gastrin has been shown to stimulate pancreatic cancer in an autocrine fashion. We hypothesized that reactivation of the peptide gastrin collaborates with KRAS during pancreatic carcinogenesis. Methods: LSL-Kra...

Objectives Hereditary primary hemochromatosis is characterized by dysregulation of iron homeostasis and is caused by a genetic predisposition to absorb too much iron from foods. Hemochromatosis has been associated with some chronic diseases, including hepatocellular carcinoma and type 2 diabetes mellitus. Type 2 diabetes is an established risk fact...

Altered regulation of endoplasmic reticulum (ER) homeostasis has been implicated in many cancers and has recently become a therapeutic and chemosensitization target of interest. We have identified Cleft Lip and Palate Transmembrane 1‐Like (CLPTM1L)/Cisplatin Resistance Related Protein 9 (CRR9) as an ER stress related mediator of cytoprotection in p...

Most expression quantitative trait locus (eQTL) studies to date have been performed in heterogeneous tissues as opposed to specific cell types. To better understand the cell-type-specific regulatory landscape of human melanocytes, which give rise to melanoma but account for <5% of typical human skin biopsies, we performed an eQTL analysis in primar...

Most expression quantitative trait loci (eQTL) studies to date have been performed in heterogeneous tissues as opposed to specific cell types. To better understand the cell-type specific regulatory landscape of human melanocytes, which give rise to melanoma but account for <5% of typical human skin biopsies, we performed an eQTL analysis in primary...

Objective Genome-wide association studies (GWAS) identify associations of individual SNPs with cancer risk but usually only explain a fraction of the inherited variability. Pathway analysis of genetic variants has been shown for many disorders to be a powerful tool in discovering novel networks of susceptibility genes. Design We have conducted a la...

Diets with high inflammatory potential are suspected to increase risk for pancreatic cancer (PC). Using pooled analyses, we examined whether this association applies to populations from different geographic regions and population subgroups with varying risks for PC, including variation in ABO blood type. Data from six case-control studies (cases, n...

This corrects the article DOI: 10.1038/ncomms15034.

In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and the United States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreat...

In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and theUnited States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreati...

Chronic inflammation increases the risk of developing one of several types of cancer. Inflammatory responses are currently thought to be controlled by mechanisms that rely on transcriptional networks that are distinct from those involved in cell differentiation. The orphan nuclear receptor NR5A2 participates in a wide variety of processes, includin...

Tissue-specific differentiation and inflammatory programmes are thought to independently contribute to disease. The orphan nuclear receptor NR5A2 is a key regulator of pancreas differentiation and SNPs in or near the human gene are associated with risk of pancreatic cancer. In mice, Nr5a2 heterozygosity sensitizes the pancreas to damage, impairs re...

We performed integrated genomic, transcriptomic, and proteomic profiling of 150 pancreatic ductal adenocarcinoma (PDAC) specimens, including samples with characteristic low neoplastic cellularity. Deep whole-exome sequencing revealed recurrent somatic mutations in KRAS, TP53, CDKN2A, SMAD4, RNF43, ARID1A, TGFβR2, GNAS, RREB1, and PBRM1. KRAS wild-t...

Background: The higher risk of pancreatic cancer in Ashkenazi Jews compared to non-Jews is only partially explained by the increased frequency of BRCA1 and BRCA2 mutations in Ashkenazi Jews. Methods: We evaluated the impact of 16 established pancreatic cancer susceptibility loci in a case-control sample of American Jews, largely Ashkenazi, inclu...

Introduction: Obesity and diabetes are two major modifiable risk factors for pancreatic cancer. Genetic variation affecting the risk of obesity- and diabetes-related pancreatic cancer have yet to be comprehensively investigated at the genome-wide level. Aims: To identify novel gene-environment interactions (GxE) of obesity/diabetes on pancreatic ca...

Objective: To elucidate the genetic architecture of gene expression in pancreatic tissues. Design: We performed expression quantitative trait locus (eQTL) and allele specific expression (ASE) analyses using RNA-sequence data and 1000 Genomes (1000G) imputed GWAS genotypes from 95 fresh frozen histologically normal pancreatic tissue samples. Data fr...

Background: Many cancers share specific genetic risk factors, including both rare high-penetrance mutations and common SNPs identified through genome-wide association studies (GWAS). However, little is known about the overall shared heritability across cancers. Quantifying the extent to which two distinct cancers share genetic origin will give insi...

Objective To elucidate the genetic architecture of gene expression in pancreatic tissues. Design We performed expression quantitative trait locus (eQTL) analysis in histologically normal pancreatic tissue samples (n=95) using RNA sequencing and the corresponding 1000 genomes imputed germline genotypes. Data from pancreatic tumour-derived tissue sa...

Genome wide association studies (GWAS) have mapped multiple independent cancer susceptibility loci to chr5p15.33. Here, we show that fine-mapping of pancreatic and testicular cancer GWAS within one of these loci (Region 2 in CLPTM1L) focuses the signal to nine highly correlated SNPs. Of these, rs36115365-C associated with increased pancreatic and t...

Background: Chromosome 8q24 has emerged as an important genetic susceptibility region for several cancers, including prostate cancer; however, little is known about the contribution of DNA methylation in this region to risk. Methods: We prospectively evaluated DNA methylation at 8q24 in relation to prostate cancer using pre-diagnostic blood samp...

Supplementary Figures and Supplementary Tables

Importance: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. Objective: To conduct a Mendelian randomization study, using germline genetic variants as instrumenta...

Recent heritability analyses have indicated that genome-wide association studies (GWAS) have the potential to improve genetic risk prediction for complex diseases based on polygenic risk score (PRS), a simple modelling technique that can be implemented using summary-level data from the discovery samples. We herein propose modifications to improve t...

Optimal P-value thresholds for including SNPs for 1D and 2D PRS in simulation studies. (DOC)

GWAS and functional annotation data for developing genetic risk prediction models. (DOC)

Optimal P-value thresholds for including SNPs for 1D and 2D PRS for five diseases with large-scale discovery data and independent validation samples. (DOC)

Prediction R2, Nagelkerke R2 and AUC in WTCCC, based on five-fold cross-validation. (DOC)

Prediction R2, Nagelkerke R2 and AUC in the three cancer GWAS data sets, based on 10-fold cross-validation. (DOC)

Additional acknowledegements. (DOC)

Prediction R2, Nagelkerke R2 and AUC for five large scale GWAS summary statistics with independent validation data. (DOC)

Calibration comparison for 1D PRS modeling with or without winner’s curse correction. (DOC)

Implication of identifying high-risk subjects based on PRS. (DOCX)

Randomly selected SNPs and SNPs related with conserved genomic regions (CR-SNPs) have different local linkage disequilibrium (LD) pattern. (TIF)