The evolution of mendelian randomization for investigating drug effects.

Dipender Gill and Stephen Burgess discuss the accompanying study by James Yarmolinsky and colleagues investigating the associations between genetically-proxied inhibition of antihypertensive drug targets and risk of common cancer subtypes using Mendelian randomization.

Personalized Cell Therapy for Patients with Peripheral Arterial Diseases in the Context of Genetic Alterations: Artificial Intelligence-Based Responder and Non-Responder Prediction.

Stem/progenitor cell transplantation is a potential novel therapeutic strategy to induce angiogenesis in ischemic tissue, which can prevent major amputation in patients with advanced peripheral artery disease (PAD). Thus, clinicians can use cell therapies worldwide to treat PAD. However, some cell therapy studies did not report beneficial outcomes. Clinical researchers have suggested that classical risk factors and comorbidities may adversely affect the efficacy of cell therapy. Some studies have indicated that the response to stem cell therapy varies among patients, even in those harboring limited risk factors. This suggests the role of undetermined risk factors, including genetic alterations, somatic mutations, and clonal hematopoiesis. Personalized stem cell-based therapy can be developed by analyzing individual risk factors. These approaches must consider several clinical biomarkers and perform studies (such as genome-wide association studies (GWAS)) on disease-related genetic traits and integrate the findings with those of transcriptome-wide association studies (TWAS) and whole-genome sequencing in PAD. Additional unbiased analyses with state-of-the-art computational methods, such as machine learning-based patient stratification, are suited for predictions in clinical investigations. The integration of these complex approaches into a unified analysis procedure for the identification of responders and non-responders before stem cell therapy, which can decrease treatment expenditure, is a major challenge for increasing the efficacy of therapies.

Genetic susceptibility to nicotine addiction: Advances and shortcomings in our understanding of the CHRNA5/A3/B4 gene cluster contribution.

Over the last decade, robust human genetic findings have been instrumental in elucidating the heritable basis of nicotine addiction (NA). They highlight coding and synonymous polymorphisms in a cluster on chromosome 15, encompassing the CHRNA5, CHRNA3 and CHRNB4 genes, coding for three subunits of the nicotinic acetylcholine receptor (nAChR). They have inspired an important number of preclinical studies, and will hopefully lead to the definition of novel drug targets for treating NA. Here, we review these candidate gene and genome-wide association studies (GWAS) and their direct implication in human brain function and NA-related phenotypes. We continue with a description of preclinical work in transgenic rodents that has led to a mechanistic understanding of several of the genetic hits. We also highlight important issues with regards to CHRNA3 and CHRNB4 where we are still lacking a dissection of their role in NA, including even in preclinical models. We further emphasize the use of human induced pluripotent stem cell-derived models for the analysis of synonymous and intronic variants on a human genomic background. Finally, we indicate potential avenues to further our understanding of the role of this human genetic variation. This article is part of the special issue on 'Contemporary Advances in Nicotine Neuropharmacology'.

Alcohol Consumption among Samoan Adults in 2010: Patterns, Correlates and Health Implications.

AIMS: We aim to describe alcohol consumption and related problems from a nationwide survey in 2010 in Samoa in association with sociodemographic variables as part of an intervention development. METHODS: The sample consisted of 3463 adults, 25-65 years of age. Participants self-reported alcohol consumption in the previous 12 months, patterns of drinking and alcohol-related psychosocial problems. Data about age, census region of residence, highest attained education level, employment, marital status, household assets score and current smoking status were gathered. RESULTS: More than one-third of men, 36.1%, and 4.1% of women consumed alcohol in the past year. There were greater proportions of alcohol users among younger adults, <45 years, in both men and women. Among men, being unemployed and residing outside of rural Savai'i and smoking cigarettes were associated with current alcohol use. Among women, tertiary education and cigarette smoking were strongly associated with alcohol use. Among alcohol consumers, almost 75% of both men and women reported being drunk more than once in the prior month, and 58% of men and 81% of women drank heavily, consuming >4 drinks for women and >5 drinks for men at least once per episode in the prior week. More men than women, 51% versus 26%, felt that alcohol consumption had interfered with their daily life. CONCLUSION: Our analyses identified correlates of alcohol consumption and associated problems that can help guide the development of targeted interventions for different sex and age groups to mitigate the social and physiological harms of alcohol misuse.

Aggressive prostate cancer phenotype and genome-wide association studies: where are we now?

The majority of prostate cancer (PCa) is indolent, however, a percentage of patients are initially diagnosed with metastatic disease, for which there is a worse prognosis. There is a lack of biomarkers to identify men at greater risk for developing aggressive PCa. Genome-wide association studies (GWAS) scan the genome to search associations of SNPs with specific traits, like cancer. To date, eight GWAS have resulted in the reporting of 16 SNPs associated with aggressive PCa (p < 5.00 × 10-2). Still, validation studies need to be conducted to confirm the obtained results as GWAS can generate false-positive results. Furthermore, post-GWAS studies provide a better understanding of the functional consequences.

A decade in psychiatric GWAS research.

After more than 10 years of accumulated efforts, genome-wide association studies (GWAS) have led to many findings, most of which have been deposited into the GWAS Catalog. Between GWAS's inception and March 2017, the GWAS Catalog has collected 2429 studies, 1818 phenotypes, and 28,462 associated SNPs. We reclassified the psychology-related phenotypes into 217 reclassified phenotypes, which accounted for 514 studies and 7052 SNPs. In total, 1223 of the SNPs reached genome-wide significance. Of these, 147 were replicated for the same psychological trait in different studies. Another 305 SNPs were replicated within one original study. The SNPs rs2075650 and rs4420638 were linked to the most replications within a single reclassified phenotype or very similar reclassified phenotypes; both were associated with Alzheimer's disease (AD). Schizophrenia was associated with 74 within-phenotype SNPs reported in independents studies. Alzheimer's disease and schizophrenia were both linked to some physical phenotypes, including cholesterol and body mass index, through common GWAS signals. Alzheimer's disease also shared risk SNPs with age-related phenotypes such as age-related macular degeneration and longevity. Smoking-related SNPs were linked to lung cancer and respiratory function. Alcohol-related SNPs were associated with cardiovascular and digestive system phenotypes and disorders. Two separate studies also identified a shared risk SNP for bipolar disorder and educational attainment. This review revealed a list of reproducible SNPs worthy of future functional investigation. Additionally, by identifying SNPs associated with multiple phenotypes, we illustrated the importance of studying the relationships among phenotypes to resolve the nature of their causal links. The insights within this review will hopefully pave the way for future evidence-based genetic studies.

Emerging applications of genome-editing technology to examine functionality of GWAS-associated variants for complex traits.

Over the last decade, genome-wide association studies (GWAS) have propelled the discovery of thousands of loci associated with complex diseases. The focus is now turning toward the function of these association signals, determining the causal variant(s) among those in strong linkage disequilibrium, and identifying their underlying mechanisms, such as long-range gene regulation. Genome-editing techniques utilizing zinc-finger nucleases (ZFN), transcription activator-like effector nucleases (TALENs), and clustered regularly-interspaced short palindromic repeats with Cas9 nuclease (CRISPR-Cas9) are becoming the tools of choice to establish functionality for these variants, due to the ability to assess effects of single variants in vivo. This review will discuss examples of how these technologies have begun to aid functional analysis of GWAS loci for complex traits such as cardiovascular disease, Type 2 diabetes, cancer, obesity, and autoimmune disease. We focus on analysis of variants occurring within noncoding genomic regions, as these comprise the majority of GWAS variants, providing the greatest challenges to determining functionality, and compare editing strategies that provide different levels of evidence for variant functionality. The review describes molecular insights into some of these potentially causal variants and how these may relate to the pathology of the trait and look toward future directions for these technologies in post-GWAS analysis, such as base-editing.

Genome-Wide Association Studies in Glioma.

Since the first reports in 2009, genome-wide association studies (GWAS) have been successful in identifying germline variants associated with glioma susceptibility. In this review, we describe a chronological history of glioma GWAS, culminating in the most recent study comprising 12,496 cases and 18,190 controls. We additionally summarize associations at the 27 glioma-risk SNPs that have been reported so far. Future efforts are likely to be principally focused on assessing association of germline-risk SNPs with particular molecular subgroups of glioma, as well as investigating the functional basis of the risk loci in tumor formation. These ongoing studies will be important to maximize the impact of research into glioma susceptibility, both in terms of insight into tumor etiology as well as opportunities for clinical translation. Cancer Epidemiol Biomarkers Prev; 27(4); 418-28. ©2018 AACRSee all articles in this CEBP Focus section, "Genome-Wide Association Studies in Cancer."

Common Genetic Variation and Breast Cancer Risk-Past, Present, and Future.

Breast cancer is the most common cancer among women in the United States, with up to 30% of those diagnosed displaying a family history of breast cancer. To date, 18% of the familial risk of breast cancer can be explained by SNPs. This review summarizes the discovery of risk-associated SNPs using candidate gene and genome-wide association studies (GWAS), including discovery and replication in large collaborative efforts such as The Collaborative Oncologic Gene-environment Study and OncoArray. We discuss the evolution of GWAS studies, efforts to discover additional SNPs, and methods for identifying causal variants. We summarize findings associated with overall breast cancer, pathologic subtypes, and mutation carriers (BRCA1, BRCA2, and CHEK2). In addition, we summarize the development of polygenic risk scores (PRS) using the risk-associated SNPs and show how PRS can contribute to estimation of individual risks for developing breast cancer. Cancer Epidemiol Biomarkers Prev; 27(4); 380-94. ©2018 AACRSee all articles in this CEBP Focus section, "Genome-Wide Association Studies in Cancer."

[From genome-wide association studies (gwas) to genome-wide polygenic scores (GPS)]. / Balayage du génome et repérage des personnes à risque - Des GWAS aux GPSChroniques génomiques.

The accumulation of extensive repositories linking phenotypic and genetic information, together with new computation methods, makes it possible to derive polygenic scores for susceptibility to common diseases that turn out to have strong predictive power. These will be clinically useful to identify individuals at high risk who may be eligible for protective interventions.

Common Genetic Variation and Susceptibility to Ovarian Cancer: Current Insights and Future Directions.

In this review, we summarize current progress in the genetic epidemiology of epithelial ovarian cancer (EOC), focusing exclusively on elucidating the role of common germline genetic variation in conferring susceptibility to EOC. We provide an overview of the more than 30 EOC risk loci identified to date by genome-wide association studies (GWAS) and describe the contribution of large-scale, cross-cancer type, custom genotyping projects, such as the OncoArray and the Collaborative Oncological Gene-Environment Study, to locus discovery and replication. We discuss the histotype-specific nature of these EOC risk loci, pleiotropy, or overlapping genetic effects between EOC and other hormone-related cancer types, and the application of findings to polygenic risk prediction for EOC. The second part of the article offers a concise review of primarily laboratory-based studies that have led to the identification of several putative EOC susceptibility genes using common variants at the known EOC risk loci as starting points. More global biological insights emerging from network- and pathway-based analyses of GWAS for EOC susceptibility are also highlighted. Finally, we delve into potential future directions, including the need to identify EOC risk loci in non-European populations and the next generation of GWAS functional studies that are likely to involve genome editing to establish the cell type-specific carcinogenic effects of EOC risk variants Cancer Epidemiol Biomarkers Prev; 27(4); 395-404. ©2018 AACRSee all articles in this CEBP Focus section, "Genome-Wide Association Studies in Cancer."

Glaucoma Genetics: Recent Advances and Future Directions.

Once considered primarily a disease of aging caused by unknown environmental influences, the notion that heritable factors could significantly contribute to the pathogenesis of sporadic glaucoma has rapidly gained traction. In part, this is due to the rapid and definitive identification of genes with strong effects on familial, earlier onset forms of glaucoma. Although the endpoint of glaucoma is irreversible optic nerve damage accompanied by blindness, the initial inciting trigger could differ. To this end, well-powered genome-wide association studies have each been conducted for primary open-angle glaucoma, primary angle-closure glaucoma, along with exfoliation syndrome and glaucoma. Each of these studies has revealed sets of significantly associated genetic loci implicating biological pathways that do not overlap between the forms of glaucoma. Although substantial biological insight has been gained from their identification, much further work remains to definitively link the implicated genetic variants with glaucoma causation. It is also hoped that the genetic findings could point us to potential routes of therapy beyond that of intraocular pressure-lowering medications or surgery.

The first decade of estrogen receptor cistromics in breast cancer.

The advent of genome-wide transcription factor profiling has revolutionized the field of breast cancer research. Estrogen receptor α (ERα), the major drug target in hormone receptor-positive breast cancer, has been known as a key transcriptional regulator in tumor progression for over 30 years. Even though this function of ERα is heavily exploited and widely accepted as an Achilles heel for hormonal breast cancer, only since the last decade we have been able to understand how this transcription factor is functioning on a genome-wide scale. Initial ChIP-on-chip (chromatin immunoprecipitation coupled with tiling array) analyses have taught us that ERα is an enhancer-associated factor binding to many thousands of sites throughout the human genome and revealed the identity of a number of directly interacting transcription factors that are essential for ERα action. More recently, with the development of massive parallel sequencing technologies and refinements thereof in sample processing, a genome-wide interrogation of ERα has become feasible and affordable with unprecedented data quality and richness. These studies have revealed numerous additional biological insights into ERα behavior in cell lines and especially in clinical specimens. Therefore, what have we actually learned during this first decade of cistromics in breast cancer and where may future developments in the field take us?

Reducing GWAS Complexity.

Genome-wide association studies (GWAS) have revealed numerous genomic 'hits' associated with complex phenotypes. In most cases these hits, along with surrogate genetic variation as measure by numerous single nucleotide polymorphisms (SNPs) that are in linkage disequilibrium, are not in coding genes making assignment of functionality or causality intractable. Here we propose that fine-mapping along with the matching of risk SNPs at chromatin biofeatures lessen this complexity by reducing the number of candidate functional/causal SNPs. For example, we show here that only on average 2 SNPs per prostate cancer risk locus are likely candidates for functionality/causality; we further propose that this manageable number should be taken forward in mechanistic studies. The candidate SNPs can be looked up for each prostate cancer risk region in 2 recent publications in 2015 (1,2) from our groups.

Advances in the translational genomics of neuroblastoma: From improving risk stratification and revealing novel biology to identifying actionable genomic alterations.

Neuroblastoma is an embryonal malignancy that commonly affects young children and is remarkably heterogenous in its malignant potential. Recently, the genetic basis of neuroblastoma has come into focus and not only has catalyzed a more comprehensive understanding of neuroblastoma tumorigenesis but also has revealed novel oncogenic vulnerabilities that are being therapeutically leveraged. Neuroblastoma is a model pediatric solid tumor in its use of recurrent genomic alterations, such as high-level MYCN (v-myc avian myelocytomatosis viral oncogene neuroblastoma-derived homolog) amplification, for risk stratification. Given the relative paucity of recurrent, activating, somatic point mutations or gene fusions in primary neuroblastoma tumors studied at initial diagnosis, innovative treatment approaches beyond small molecules targeting mutated or dysregulated kinases will be required moving forward to achieve noticeable improvements in overall patient survival. However, the clonally acquired, oncogenic aberrations in relapsed neuroblastomas are currently being defined and may offer an opportunity to improve patient outcomes with molecularly targeted therapy directed toward aberrantly regulated pathways in relapsed disease. This review summarizes the current state of knowledge about neuroblastoma genetics and genomics, highlighting the improved prognostication and potential therapeutic opportunities that have arisen from recent advances in understanding germline predisposition, recurrent segmental chromosomal alterations, somatic point mutations and translocations, and clonal evolution in relapsed neuroblastoma.

Neuroblastoma.

Neuroblastoma is the most common extracranial solid tumor in children. Since its first description some 150 years ago, its enigmatic clinical presentation has challenged clinicians and fascinated basic researchers. This article presents an overview of the key clinical features of neuroblastoma and current therapeutic approaches. It also highlights how our understanding of sympathoadrenal developmental biology, coupled with transcriptome analyses, next-generation sequencing, and genome-wide association and epigenetic studies, has illuminated critical signal transduction pathways involved in neuroblastoma tumorigenesis and identified therapeutically tractable targets for clinical development.

Genetic markers associated with cutaneous adverse drug reactions to allopurinol: a systematic review.

Pharmacogenomic markers in the HLA coding genes have been associated with drug hypersensitivity of multiple drugs, including allopurinol. In this systematic review, we summarize the pharmacogenomic evidence available regarding allopurinol-induced cutaneous adverse drug reactions (cADRs). We found that the HLA-B*5801 allele was significantly associated with the risk of severe cADRs in the Han Chinese, Korean, Thai, Japanese and European populations. The association between less severe cADRs and HLA-B*5801 was less consistent. All SNPs identified in genome-wide association studies of common variants were also located in or nearby HLA-B*5801. Future studies should focus on more common but less severe allopurinol-induced cADRs, as well as the potential role of rare variants as predictors of these cADRs.

Surgery in the era of the 'omics revolution.

BACKGROUND: Surgery is entering a new phase with the revolution in genomic technology. Cheap, mass access to next-generation sequencing is now allowing the analysis of entire human genomes at the DNA and RNA level. These data sets are being used increasingly to identify the molecular differences that underlie common surgical diseases, and enable them to be stratified for patient benefit. METHODS: This article reviews the recent developments in the molecular biology of colorectal, oesophagogastric and breast cancer. RESULTS: The review specifically covers developments in genetic predisposition, next-generation sequencing studies, biomarkers for stratification, prognosis and treatment, and other 'omics technologies such as metabolomics and proteomics. CONCLUSION: There are unique opportunities over the next decade to change the management of surgical disease radically, using these technologies. The directions that this may take are highlighted, including future advances such as the 100,000 Genomes Project.

Down the line from genome-wide association studies in inflammatory bowel disease: the resulting clinical benefits and the outlook for the future.

Inflammatory bowel disease (IBD), consisting of Crohn's disease and ulcerative colitis, is a chronic inflammatory disease of the gut. The etiology of IBD is complex, involving genetic as well as environmental factors. Genetic studies have identified 163 genetic risk loci for IBD, which have led to new insights into the biological mechanisms of the disease. The currently known IBD risk loci show an almost 75% overlap with genetic risk loci for other immune mediated diseases. Current studies are focused on the translation of the identified risk loci to clinical practice. The first steps towards this translation are being taken with the identification of genetic risk factors for drugs toxicity, specific disease course and response to therapy. In this review we will discuss how the IBD genetic risk loci were identified and how this knowledge can be translated towards clinical practice.