Rare and common variant discovery in complex disease: the IBD case study.

Complex diseases such as inflammatory bowel disease (IBD), which consists of ulcerative colitis and Crohn's disease, are a significant medical burden-70 000 new cases of IBD are diagnosed in the United States annually. In this review, we examine the history of genetic variant discovery in complex disease with a focus on IBD. We cover methods that have been applied to microsatellite, common variant, targeted resequencing and whole-exome and -genome data, specifically focusing on the progression of technologies towards rare-variant discovery. The inception of these methods combined with better availability of population level variation data has led to rapid discovery of IBD-causative and/or -associated variants at over 200 loci; over time, these methods have grown exponentially in both power and ascertainment to detect rare variation. We highlight rare-variant discoveries critical to the elucidation of the pathogenesis of IBD, including those in NOD2, IL23R, CARD9, RNF186 and ADCY7. We additionally identify the major areas of rare-variant discovery that will evolve in the coming years. A better understanding of the genetic basis of IBD and other complex diseases will lead to improved diagnosis, prognosis, treatment and surveillance.

The SNP-Based Heritability - A Commentary on Yang et al. (2010).

I write this commentary as a part of a special issue published in this journal to celebrate Nick Martin's contribution to the field of human genetics. In this commentary, I briefly describe the background of the Yang et al. (2010) study and show some of the unpublished details of this study, its contribution to tackling the missing heritability problem and Nick's contribution to the work.

Genetics of Biochemical Phenotypes.

Biomarkers diagnose, predict or assess the risk of disease, and studies of the effects of genetic variation on biomarker phenotypes in the general population complement studies on patients diagnosed with disease. This paper traces the evolution of studies on biomarker genetics over the past 40 years through examples drawn from the work of Professor Martin and his colleagues.

Curly Questions.

This letter reflects on my collaborations with Nick Martin over the past 18 years. Working together we have applied twin-family and statistical genetics methods to examine the genetic architecture and identify genetic variants influencing a range of physical, psychological and social traits. The common thread across much of this work has been the empirical questions: Why are we the way we are and how can this knowledge help us when things go wrong?

Migraine, Human Genetics and a Passion for Science.

This note reflects on my collaborations with Nick Martin and the GenEpi group over the past 20 years. Over the past two decades, our work together has focused on gene mapping and understanding the genetic architecture of a wide range of traits with particular foci on migraine and common baldness. Our migraine research has included latent class and twin analyses cumulating in genome-wide association analyses which had identified 44 (34 new) risk variants for migraine. Leveraging these results through polygenic risk score analyses identified subgroups of patients likely to respond to triptans (an acute migraine drug), providing the first step toward precision medicine in migraine [Kogelman et al. (2019) Neurology Genetics, 5, e364].

The Genetics of Reading and Language.

Recounts how our collaboration with Nick Martin was shaped over two decades, leading to the first studies of predictions from the 'Dual Route Cascaded' computational model of reading in twins, and extending into the molecular work, first linkage, fine mapping of genes identified in pedigree studies, into now the genomewide association study era and the first polygenic risk scores for reading and their potential in early clarifying causality and validating interventions, as well as for future global collaborations in improving these predictors and identifying causal variants. We highlight Nick's warm, future-focused optimism, support and inclusive approach without which none of this would have been possible. The circle of Nick asking, over half a century ago, 'What genes do you think make some kids get better grades?' has built a diverse scientific legacy involving thousands of papers and collaborations. The (heritable) traits of curiosity, boldness, warmth, interest in societally important questions, openness to new methods, ambition and collaborative skill to bring into being the infrastructure and samples needed for this research are rare, and we are grateful.

ANGI - Anorexia Nervosa Genetics Initiative.

Identification of genetic variants associated with eating disorders is underway. The Anorexia Nervosa Genetics Initiative, an initiative of the Klarman Family Foundation, has contributed to advancing the field, yielding a large-scale genome-wide association study published in Nature Genetics. Eight genetic variants significantly associated with anorexia nervosa were identified, along with patterns of genetic correlations that suggest both psychiatric and metabolic origins of this serious and life-threatening illness. This article details the role of Professor Nick Martin in contributing to this important collaboration.

A Brief History of the Collaboration between Dr Nathan Gillespie and Professor Nick Martin Including Personal Reflections.

This article describes Dr Nathan Gillespie's PhD training and supervision under Professor Nick Martin and their ongoing collaborations. Drs Gillespie and Martin have collaborated on numerous biometrical genetic analyses applied to cross-sectional and longitudinal twin data, combined molecular and phenotypic modeling, as well as genomewide meta-analyses of psychoactive substance use and misuse. Dr Gillespie remains an active collaborator with Professor Martin, including ongoing data collection, analysis and publications related to the Brisbane Longitudinal Twin Study.

Cohorts.

Cohort studies are essential for conducting large studies of multiple exposures and outcomes in humans. Recently, the ability to combine data from multiple cohorts in, for example, meta-analyses, and the willingness in the genetics community to collaborate to enable replication studies has led to many new insights into the genetic and environmental determinants of human health and behaviors. The contribution of Professor Nicholas Martin to the development of cohort studies, particularly of twin and twin-family studies, over a period of several decades is reviewed. He has contributed to the development and use of both Australian and international resources. The contributions of Australian twin studies to genomewide association projects are multiple, and across multiple domains, from biomarkers, lifestyle and behavior to disorders and disease.

Evaluating historical candidate genes for schizophrenia.

Prior to the genome-wide association era, candidate gene studies were a major approach in schizophrenia genetics. In this invited review, we consider the current status of 25 historical candidate genes for schizophrenia (for example, COMT, DISC1, DTNBP1 and NRG1). The initial study for 24 of these genes explicitly evaluated common variant hypotheses about schizophrenia. Our evaluation included a meta-analysis of the candidate gene literature, incorporation of the results of the largest genomic study yet published for schizophrenia, ratings from informed researchers who have published on these genes, and ratings from 24 schizophrenia geneticists. On the basis of current empirical evidence and mostly consensual assessments of informed opinion, it appears that the historical candidate gene literature did not yield clear insights into the genetic basis of schizophrenia. A likely reason why historical candidate gene studies did not achieve their primary aims is inadequate statistical power. However, the considerable efforts embodied in these early studies unquestionably set the stage for current successes in genomic approaches to schizophrenia.

Five years of GWAS discovery.

The past five years have seen many scientific and biological discoveries made through the experimental design of genome-wide association studies (GWASs). These studies were aimed at detecting variants at genomic loci that are associated with complex traits in the population and, in particular, at detecting associations between common single-nucleotide polymorphisms (SNPs) and common diseases such as heart disease, diabetes, auto-immune diseases, and psychiatric disorders. We start by giving a number of quotes from scientists and journalists about perceived problems with GWASs. We will then briefly give the history of GWASs and focus on the discoveries made through this experimental design, what those discoveries tell us and do not tell us about the genetics and biology of complex traits, and what immediate utility has come out of these studies. Rather than giving an exhaustive review of all reported findings for all diseases and other complex traits, we focus on the results for auto-immune diseases and metabolic diseases. We return to the perceived failure or disappointment about GWASs in the concluding section.

Single gene disorders come into focus--again.

In the early 1990s, when the second 5-year plan for the Human Genome Project-which requested more money than any previous research project in biology-was written, common disorders were presented as the future target of genome research. This was a clever move to ensure continued public support for this endeavor, which had been justified previously by the prospect that it would lead to the diagnosis, prevention, and therapy of severe, but mostly rare, Mendelian disorders. Today, more than 15 years later, after billions of dollars have been spent on genome-wide association studies (GWAS), very few major genetic risk factors for common diseases have been identified, and the enthusiasm for large GWAS is dwindling. At the same time, there is renewed interest for studying single gene disorders, which are now considered by some as a better clue to the understanding of common diseases. While this is probably true, Mendelian disorders are also important in their own right, since they must be far more common than generally thought. As discussed here, various efficient strategies exist for the elucidation of single gene defects, and their systematic application in combination with novel genome partitioning and massive parallel sequencing techniques, will have far-reaching implications for health care.

[End of the road for the « homosexuality gene ¼]. / Clap de fin pour le « gène de l'homosexualité ¼ - Chroniques génomiques.

Evidence for a "homosexuality gene" was claimed in the early 1990's on the basis of linkage studies that, by current criteria, were woefully underpowered. Indeed, follow up studies gave contradictory results. Genome-wide association studies, and very large databases with detailed genetic and phenotypic data, have made possible a re-examination of this issue. While modest heritability (ca. 0.3) for homosexuality is confirmed, no major locus is found and the genetic influence appears extremely polygenic. Thus, there is no single gene, or even small set of genes, that have a strong influence on homosexuality.

From R.A. Fisher's 1918 Paper to GWAS a Century Later.

The genetics and evolution of complex traits, including quantitative traits and disease, have been hotly debated ever since Darwin. A century ago, a paper from R.A. Fisher reconciled Mendelian and biometrical genetics in a landmark contribution that is now accepted as the main foundation stone of the field of quantitative genetics. Here, we give our perspective on Fisher's 1918 paper in the context of how and why it is relevant in today's genome era. We mostly focus on human trait variation, in part because Fisher did so too, but the conclusions are general and extend to other natural populations, and to populations undergoing artificial selection.

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 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."

A Decade of GWAS Results in Lung Cancer.

Genome-wide association studies (GWAS) were successful to identify genetic factors robustly associated with lung cancer. This review aims to synthesize the literature in this field and accelerate the translation of GWAS discoveries into results that are closer to clinical applications. A chronologic presentation of published GWAS on lung cancer susceptibility, survival, and response to treatment is presented. The most important results are tabulated to provide a concise overview in one read. GWAS have reported 45 lung cancer susceptibility loci with varying strength of evidence and highlighted suspected causal genes at each locus. Some genetic risk loci have been refined to more homogeneous subgroups of lung cancer patients in terms of histologic subtypes, smoking status, gender, and ethnicity. Overall, these discoveries are an important step for future development of new therapeutic targets and biomarkers to personalize and improve the quality of care for patients. GWAS results are on the edge of offering new tools for targeted screening in high-risk individuals, but more research is needed if GWAS are to pay off the investment. Complementary genomic datasets and functional studies are needed to refine the underlying molecular mechanisms of lung cancer preliminarily revealed by GWAS and reach results that are medically actionable. Cancer Epidemiol Biomarkers Prev; 27(4); 363-79. ©2018 AACRSee all articles in this CEBP Focus section, "Genome-Wide Association Studies in Cancer."