Alzheimer's - Dementia, Author Interviews, Genetic Research, JAMA, Stanford / 07.11.2023 Interview with: Michael E. Belloy, PhD Department of Neurology and Neurological Sciences Stanford University, Stanford, California What is the background for this study? Response: Apolipoprotein E (APOE)*2 and APOE*4 are, respectively, the strongest protective and risk-increasing, genetic variants for late-onset Alzheimer disease. As such, one’s APOE genotype is highly relevant towards clinical trial design and Alzheimer’s disease research. However, most insights so far are focused on the associations of these APOE genotypes with Alzheimer’s disease risk in non-Hispanic white individuals. One important aspect of our work is that we really increased sample sizes for non-Hispanic Black, Hispanic, and East Asian individuals, so that we now have better understanding of the associations of APOE genotypes with Alzheimer’s disease risk in these groups. In complement, we also did the largest investigation to date on the role of ancestry on the associations of APOE genotypes with Alzheimer’s disease risk. The scale of our study was thus a critical factor in generating novel insights. (more…)
Author Interviews, Genetic Research, Melanoma / 06.10.2023 Interview with: Dr Mitchell Stark B.App.Sc (Hons), PhD UQ Amplify Senior Research Fellow Skin Cancer Genomics and Biomarker Discovery Group Leader Frazer Institute Faculty of Medicine The University of Queensland Translational Research Institute Woolloongabba, QLD 4102 What is the background for this study? What are the main findings? Response: Nodular melanoma (NM) is one of the most aggressive subtypes of melanoma. Despite making up only 14 per cent of cases, it is the largest contributor to melanoma deaths. Nodular melanoma is difficult to catch early because it grows fast and has often spread deeper in the skin by the time it’s diagnosed. Around a quarter of NM cases also appear as a skin-coloured tumour, which might go unnoticed for longer. In this study we wanted to determine whether there were genetic variants associated with nodular melanoma, which might contribute to nodular melanoma risk. We identified 39 genes with rare DNA variants which had the greatest frequency in nodular melanoma patients compared to non-NM patients. (more…)
Aging, Author Interviews, Lancet, Medical Imaging, Technology / 24.08.2023 Interview with: Dr. Daiju Ueda Department of Diagnostic and Interventional Radiology Graduate School of Medicine Osaka Metropolitan University Osaka, Japan What is the background for this study? Response:  We were inspired by the potential of chest radiography as a biomarker for aging. Previous research had utilized chest radiographs for age estimation, but these studies often involved cohorts with diseases. (more…)
Author Interviews, Biomarkers, Gastrointestinal Disease / 16.08.2023 Interview with: Daniel L. Worthley MBBS (Hons), PhD, MPH, FRACP, AGAF Gastroenterologist Associate Professor University of Adelaide What is the background for this study? Response: Cells are revolutionising healthcare, from modern faecal microbial transplantation in the gut to CAR-T cells fighting cancers, life healing life. Some aspects of cellular care are so entrenched in medicine that they are almost overlooked for the miraculous cellular therapies that they are, such as stem cell transplantation to treat haematological malignancies and, of course, in vitro fertilization, life creating life. Modern medicine is slowly, but surely, pivoting from pills to cells. Professor Siddhartha Mukherjeee, oncologist, scientist, and author, provides a beautiful thesis of this in his book Song of the Cell and in his TED talk on the cellular revolution in medicine ( I was lucky enough to have trained with Sid as a post-doc at Columbia and this concept was really drummed into me. But, as a gastroenterologist, perhaps it was the bacterial cells, rather than the blood cells, that had most to offer in the management of bowel disorders? Around the same time, Professors Jeff Hasty, Tal Danino and Omar Din from UC San Diego had been inventing and publishing, in my opinion, the best bacterial engineering work that has ever been produced to specifically target cancer. I remember when we first reviewed their 2016 Nature paper in our lab meeting (, it was like – “We gotta meet these guys!”. Through Tal, who was by then, working at Columbia, I was introduced to Jeff and I attended his lab meeting back in 2019. That was where our project began after a lab meeting in La Jolla. Rob Cooper had presented his work on horizontal gene transfer. Everything that comes out of Jeff’s lab is both practical and reproducible but also beautiful. Beautiful in a scientific self-evident way that instantly communicates the purpose, approach and outcomes of an experiment. Rob’s presentation that day was a case-in-point. Rob was studying genes and gene transfer in bacteria (see part of Rob’s fascinating presentation here, Genes are the fundamental unit of heredity and gene transfer (or inheritance) the process by which genes are passed from one cell to another. Genes may be inherited vertically when one cell replicates its DNA and divides into two, now separate, cells (reproduction). Genes are the stuff, and vertical gene transfer is the process, by which you receive your mother’s laugh and your father’s eyebrows. Genes may also, however, be inherited horizontally when DNA is passed between unrelated cells, outside of parent to offspring inheritance. Horizontal gene transfer is quite common in the microbial world. Certain bacteria can salvage genes from cell-free DNA found within its environment. This sweeping up of cell-free DNA, into a cell, is called natural competence. So, competent bacteria can sample their nearby environment and, in doing so, acquire genes that may provide a selective advantage to that cell. Like cellular panning for flecks of gold in a stream. After Rob’s presentation, Jeff, Rob and I started to discuss the possibilities. If bacteria can take up DNA, and cancer is defined genetically by a change in its DNA then, theoretically, bacteria could be engineered to detect cancer. Colorectal cancer seemed a logical proof of concept as the colorectal lumen is full of microbes and, in the setting of cancer, full of tumour DNA.  When a biophysicist, a scientist and a gastroenterologist walk into a bar, after a lab meeting, this is what can happen! Professor Susi Woods and Dr Josephine Wright, superb cancer scientists from Adelaide, Australia, were quickly recruited in as essential founding members of the group. We all got to work. Australian and US grants, lots of experiments, early morning Zoom calls across the Pacific, inventing new animal models and approaches, i.e. a many year, iterative process of design-build-test-learn, that got us all to where we are now. (more…)
Alzheimer's - Dementia, Author Interviews, Genetic Research / 14.06.2023 Interview with: Alexandra M Whiteley PhD Department of Biochemistry University of Colorado Boulder Boulder, Colorado What is the background for this study? Response: My laboratory was interested in understanding how UBQLN2 maintains cellular health. Ubiquilins facilitate protein degradation, but the precise proteins that they help to break down were not well understood. UBQLN2 is of particular interest because mutations in the UBQLN2 gene lead to a familial form of ALS. This project, which was published in eLife this year, stems from work that was published when I was a postdoctoral researcher at Harvard Medical School, where we found a link between UBQLN2 and the virus-like protein PEG10. Now at the University of Colorado, Boulder, my laboratory has focused on trying to understand this connection between the two proteins, and how PEG10 could contribute to ALS. (more…)
ASCO, Author Interviews, Cancer Research, Genetic Research, JAMA, Race/Ethnic Diversity, Stanford / 06.06.2023 Interview with: Allison W. Kurian, M.D., M.Sc. Professor of Medicine and of Epidemiology and Population Health Associate Chief, Division of Oncology Co-Leader, Population Sciences Program, Stanford Cancer Institute Director, Women’s Clinical Cancer Genetics Program Stanford University School of Medicine Stanford, CA 94305-5405 What is the background for this study? What types of cancers were in the study? Response: Genetic testing for cancer risk is increasingly important after a cancer diagnosis, to inform use of targeted therapies, secondary cancer prevention approaches and cascade genetic testing of family members. However, very little is known about how genetic testing is used after a cancer diagnosis at the population level. We leveraged a very large population-based data resource, the Surveillance, Epidemiology and End Results (SEER) cancer registries of the states of California and Georgia, and linked data from these registries to clinical genetic testing results provided by the four major laboratories that provide such testing. We used this linked registry-genetic testing dataset to study adults (age >=20 years) diagnosed with all types of cancer in the states of Georgia and California from 2013-2019. (more…)
Author Interviews, Genetic Research, PNAS, UCSD / 20.04.2023 Interview with: Chinmay Kalluraya a Selma and Robert Silagi Award for Undergraduate Excellence winner UC San Diego and now a graduate student at MIT and Matt Daugherty  Ph.D Associate Professor University of California, San Diego Department of Molecular Biology, School of Biological Sciences La Jolla CA, 92093-0377 What is the background for this study? Would you explain the role of retinoid-binding protein? eye, visionResponse: We were broadly interested in discovering instances of bacterial genes that have been acquired by diverse animal genomes over millions of years of evolution by the process of horizontal gene transfer (HGT). Since these events are quite rare and most previous discoveries have been serendipitous, we developed computational methods to identify genes acquired by HGT in animals. One of the exciting discoveries from our work was that vertebrate IRBP appeared to have originated in bacteria and is now a critical component of the vertebrate visual cycle, so this paper focuses on that one discovery. IRBP or interphotoreceptor retinoid binding protein is an important protein present in the space between two major cell types in our eyes, photoreceptor cells and RPE cells. Our ability to see involves an intricate set of steps where light is first sensed by causing a change (isomerization) in the chemical structure of molecules in the eye called retinoids. This sensing of light occurs in our photoreceptor cells. Following this change in the chemical structure, the retinoid needs to be recycled back to the chemical structure that can again sense light. This recycling occurs in RPE cells. IRBP performs the essential function of shuttling retinoids between the photoreceptors and the RPE cells, which allows the cycle of sensing and regeneration to work. Supporting its importance, mutations in IRBP (also known as retinol binding protein 3 or RBP3) can cause several severe human eye diseases. (more…)
Addiction, Author Interviews, Genetic Research, Nature / 29.03.2023 Interview with: Alexander S. Hatoum, PhD Research Assistant Professor Institute for Behavioral Genetics Washington University in St. Louis What is the background for this study? Response: It is well known that someone with one substance use disorder will have another sometime in their lifetime or concurrently.  Further, individuals that do manifest two or more substance use disorders in their lifetime have the most morbid conditions. However, research often ignores the comorbidity and focuses on diagnosis of one substance use disorder at a time (i.e. opioid use disorder or alcohol use disorder). We set out to identify the biology behind the cross-substance liability. (more…)
Author Interviews, Genetic Research / 21.03.2023 Interview with: Ernest Turro, PhD Associate Professor Genetics and Genomics Sciences The Turro group runs a research program on statistical genomics, with a dual focus on rare diseases and blood-related traits at the Icahn School of Medicine Mount Sinai Health System What is the background for this study? Would you describe the Rareservoir database? Response:   The main motivation for our work is that only half of the approximately 10,000 catalogued rare diseases have a resolved genetic cause (or aetiology). Patients with these diseases are unable to obtain a genetic diagnosis which could otherwise inform prognosis, treatment for themselves and affected relatives. One route towards resolving the remaining aetiologies is to enroll large numbers of rare disease patients into research studies so that statistical analyses can be performed comparing the genetic with the clinical characteristics of the study participants. One major endeavour, the 100,000 Genomes Project (100KGP), sequenced the genomes and collected clinical phenotype data for 34,523 UK patients and 43,016 unaffected relatives across 29,741 families. The scale of this study is unprecedented, partly thanks to the ever-decreasing cost of DNA sequencing (25 years ago, it cost $1bn to sequence a whole genome, while now it costs only a few hundred dollars). Working with such large datasets is notoriously cumbersome. To overcome this, we developed a computational approach (the Rareservoir) that distills the most important information into a relatively small database, allowing us to apply our statistical methods nimbly. We noted that the "genetic variants" that cause rare diseases are typically kept rare in the human population by natural selection because affected individuals tend to have few children, if any. This meant that we could discard the genetic information corresponding to variants that are common in the human population without throwing away the key disease-causing variants. By focussing on these "rare variants", we were able to perform our analyses using a small database (a `Rareservoir’), only 5.5GB in size, hastening our progress significantly. (more…)
Author Interviews / 10.03.2023 Interview with: Norman Kleiman, PhD, MS Department of Environmental Health Sciences Mailman School of Public Health Columbia University, New York, NY What is the background for this study? Response: The 1986 Chornobyl nuclear disaster caused the evacuation of 300,000 persons from the cities and villages surrounding the nuclear power plant complex. Pets and belongings were left behind, and the Soviet authorities ordered all animals within the Chornobyl Exclusion Zone killed. Some dogs evaded destruction, and some 300+ descendants of these animals live primarily at two locations today, immediately surrounding the Nuclear Power Plant (NPP) complex and about 10 km away in Chornobyl city. What is relatively unknown to the general public is that Chornobyl is not a desolate, abandoned wasteland. Some thousands of individuals work there every day in continuing cleanup activities and at two new fuel reprocessing facilities built near the damaged reactor. These areas have been substantially remediated, and the average radiation levels are relatively modest. The dogs, which, while feral, are accustomed to human interaction, live near the workers and are not currently exposed to high radiation levels. In contrast to lower radiation levels, there is a toxic mixture of heavy metals, organics, pesticides, and unknown chemicals left over from years’ long cleanup efforts and the decay of a large former military-industrial complex at the NPP. Since 2016, the NPP authorities have brought in teams of veterinarians and volunteers to spay, neuter, and vaccinate the dogs to protect the workers and deal with a growing population. At the same time, some scientists joined the teams to obtain various kinds of biospecimens (hair, urine, feces, blood, saliva, parasites) to examine the animals’ health and learn how this toxic environment may have affected them or their offspring. Since dogs are human companion animals and live closely with us, any information we learn about health risks to the dogs may be relevant to protecting human workers and inform us about the kinds of health risks posed by ecological and environmental disasters in the future. (more…)
Alzheimer's - Dementia, Author Interviews, Genetic Research, Race/Ethnic Diversity, Stanford / 21.02.2023 Interview with: Yann Le Guen, Ph.D. Assistant Director, Computational Biology Quantitative Sciences Unit Stanford Medicine What is the background for this study? Response: Apart from aging, the strongest contributing factor for late-onset Alzheimer’s disease is a specific allele of the APOE gene, which has three common alleles E2, E3, and E4. While E3 is the most common and considered as the reference, E2 is associated with decreased Alzheimer’s disease risk and E4 is associated with increased Alzheimer’s disease risk. Notably the prevalence of E4 among Alzheimer’s patient is high with about 60% of these carrying at least one E4 allele, while solely about 30% Americans carry one E4 allele. It’s worth emphasizing that individuals with an E4/E4 genotype have an exponential increased in their risk to develop AD (10 times as likely than the reference E3/E3 genotype), and individuals with an E3/E4 genotype have an intermediate risk. Though, most studies of Alzheimer’s disease genetic have been focused on European ancestry, this is beginning to change thanks to NIH’s efforts to fund more studies in non-European ancestry individuals. Our study built on these recent efforts to assess the Alzheimer disease risk associated with an APOE variant (R145C) present in about ~4% African Americans, but extremely rare in Europeans. (more…)
Author Interviews, Genetic Research, NIH, Pediatrics / 20.02.2023 Interview with: Natalie Shaw, M.D., MMSc. Principal Investigator Head of the Pediatric Neuroendocrinology Group Dr. Shaw holds a secondary appointment in NIEHS Reproductive and Developmental Biology Laboratory. What is the background for this study? Would you briefly describe the two affected conditions? Dr. Shaw: Congenital arhinia is a rare congenital malformation characterized by the complete absence of an external nose and internal olfactory (smell) structures.  It is frequently associated with eye and reproductive defects.  Facioscapulohumeral muscular dystrophy (FSHD) type 2 is a form of muscular dystrophy that presents in young adulthood.  Both conditions are caused by mutations in the gene SMCHD1.  In FSHD type 2, we know that loss of SMCHD1 activity leads to expression of a toxic protein called DUX4 in muscle.  The cause of arhinia was unknown. (more…)
Author Interviews, Genetic Research, JAMA, Karolinski Institute, Weight Research / 31.01.2023 Interview with: Lisa Dinkler, Ph.D. | Postdoctoral researcher Center for Eating Disorders Innovation (CEDI) Department of Medical Epidemiology and Biostatistics Karolinska Institutet, Stockholm What is the background for this study? Response: Avoidant restrictive food intake disorder (ARFID) is a relatively recently defined eating disorder. Affected people severely restrict their food intake in terms of total amount or variety. This leads to serious physical, psychological, and social consequences such as weight loss, nutritional deficiencies, and social isolation. Compared to people with other eating disorders – such as anorexia nervosa, bulimia nervosa, and binge-eating disorder – food restriction in people with ARFID is not driven by body dissatisfaction or the desire to lose weight. Despite how serious ARFID is, we still know very little about what causes it – making it difficult to develop effective treatments. We do know that genetic factors contribute significantly to the development of other eating disorders (so-called heritability), but we did not yet know to which degree genetic factors play a role in the development of ARFID. We therefore conducted the first twin study of ARFID, using a sample of ~34,000 Swedish twins including ~700 children with ARFID. (more…)
Author Interviews, Genetic Research, Infections, Neurological Disorders / 14.12.2022 Interview with: Dr. Eli Hatchwell, MA MB BChir (Cantab) DPhil (Oxon) BA (OU) Chief Scientific Officer Population Bio UK, Inc. Begbroke Science Park Begbroke Hill Begbroke, Oxfordshire United Kingdom What is the background for this study? Response: Progressive Multifocal Leukoencephalopathy (PML) is a devastating condition that is associated with a number of clinical situations, including treatment with a variety of drugs. Of these, the best known is natalizumab (Tysabri), which is a very successful drug in the treatment of MS (multiple sclerosis). Only a small proportion of patients treated with natalizumab develop PML and this has always been a mystery. The study was based on a hypothesis that some individuals have an underlying susceptibility to developing PML, based on the presence of variants in genes that are important in the immune system. The study identified several of these variants. (more…)
Author Interviews, COVID -19 Coronavirus, PLoS, Rheumatology / 04.11.2022 Interview with: Professor Tim Vyse Professor of Molecular Medicine and Dr David Morris Non Clinical Lecturer in Molecular Genetics Guy’s Hospital, London What is the background for this study? What are the main findings? Response: We observed a correlation between the genetic associations with severe COVID-19 and those with systemic lupus erythematosus (SLE, Lupus), and aimed to discover which genetic loci were shared by these diseases and what biological processes were involved. This resulted in the discovery of several genetic loci, some of which had alleles that were risk for both diseases and some of which were risk for severe COVID-19 yet protective for SLE. The locus with most evidence of shared association (TYK2) is involved in interferon production, a process that is important in response to viral infection and known to be dysregulated in SLE patients.  Other shared associated loci contained genes also involved in the defense response and the immune system signaling. These results add to the growing evidence that there are alleles in the human genome that provide protection against viral infection yet are risk for autoimmune disease. (more…)
Author Interviews, Cancer Research, Colon Cancer, Genetic Research, Nature / 18.10.2022 Interview with: Royce Zhou, MD/PhD Candidate Icahn School of Medicine at Mount Sinai What is the background for this study? Response: The background of this story is to see whether things outside of the cancer cell, such as the tumor microenvironment, can lead to epigenetic changes within the cancer cell. These changes are largely believed to be due to factors inside the cell, not outside. Super-enhancers are the top 1-2% of enhancers in the genome. They control cell identity genes and oncogenes in cancer. (more…)
Author Interviews, Exercise - Fitness, Genetic Research, Lifestyle & Health, Nature / 08.09.2022 Interview with: Marcel den Hoed, PhD Researcher,Department of Immunology, Genetics and Pathology Uppsala University What is the background for this study? What are the main findings? Response: In this paper we performed a multi-ancestry meta-analysis of 51 genome-wide association studies, in data from over 700,000 individuals. This yielded 11 DNA regions that are robustly associated with self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA), and 88 DNA regions for self-reported leisure screen time (LST). Around half of the identified DNA regions are also associated with objectively assessed physical activity traits in data from the UK Biobank. Causal inference using a Mendelian randomization approach subsequently showed bidirectional causal effects between LST and body mass index (BMI), with the effect of LST on BMI being 2-3-fold larger than vice versa. Less LST and more MVPA protect from diabetes, attention deficit hyperactivity disorder, depression, and earlier age at death, with all causal effects of MVPA and leisure screen time being mediated or confounded by BMI. Further analyses showed that DNA regions associated with LST are more often located close to genes whose expression in skeletal muscle is altered by strength training than expected by chance, suggesting that these genes may influence the likelihood of adopting an active lifestyle by influencing the response to training. (more…)
Author Interviews, Genetic Research, Heart Disease / 04.08.2022 Interview with: Christine Seidman, MD Thomas W. Smith Professor of Medicine and Genetics Director, CV Genetics Center Brigham and Women’s Hospital Harvard Medical School Dept of Genetics Boston, MA 02115  What is the background for this study?    Response: Heart failure is a common and incurable disorder that is known to arise from many different underlying causes.  By exploiting a new technology, single nuclear transcriptional analyses, we aimed to define molecular profiles in human hearts tissues that were obtained from patients with different genetic and non-genetic causes of heart failure. Our goal was to determine if there were distinctive signatures that could provide new opportunities to develop precise treatments, based on the specific cause of heart failure. (more…)
Aging, Alzheimer's - Dementia, Author Interviews, Brigham & Women's - Harvard, Genetic Research, Nature / 20.04.2022 Interview with: Michael B. Miller, MD, PhD Instructor, Harvard Medical School Department of Pathology Brigham and Women's Hospital  What is the background for this study? Would you explain what is meant by somatic genetic changes and how they might occur?  Response: Changes, also called mutations, in the DNA sequence of genes can be passed from parents to their children, and explain why many diseases run in families. This kind of DNA change is called a germline mutation and is present in every cell in a person’s body. Gene mutations can also occur in a subset of cells of a person, in which case they are called somatic mutations. Somatic mutations are well known as a cause of cancer, and recent research has found that somatic mutations can also happen in non-cancerous cells that appear otherwise normal. Recent studies have even found that somatic mutations are present in neurons, cells in the brain that transmit electrical signals and play an important role in how the brain functions. Furthermore, in neurons, somatic mutations increase with age, so we set out to understand if somatic mutations might be playing a role in age-related brain diseases like Alzheimer’s. (more…)
Author Interviews, Brigham & Women's - Harvard, Cancer Research, Genetic Research, Nature / 18.04.2022 Interview with: Jason Vassy, MD, MPH Brigham and Women's Hospital Division of General Internal Medicine & Primary Care Brigham’s Precision Population Health at Ariadne Labs and VA Boston  What is the background for this study?    Response: A person’s risk of developing diseases such as type 2 diabetes or breast cancer may be influenced by thousands of genetic differences, the effects of which can be combined to derive a single score, often called a polygenic risk score (PRS). PRS might be useful to help patients and their physicians make tailored decisions about their health care, but several challenges to the clinical implementation of PRS remain. Most importantly, most PRS are less accurate in individuals of non-European descent, since most genomic research to date has been conducted in European populations. Another key challenge is that physicians and patients will need support to understand polygenic risk score and use them to make medical decisions. Clinical guidelines do not yet exist to help a physician know whether and how they should treat a patient with a high-risk score differently than an average-risk patient. We designed the Genomic Medicine at VA (GenoVA) Study to address some of these challenges. (more…)
Author Interviews, Genetic Research, Sleep Disorders, UCSF / 20.03.2022 Interview with: Ying-Hui Fu, PhD Professor, Neurology Weill Institute for Neurosciences UCSF  What is the background for this study?  Response: Most people are aware that a lack of sleep is associated with all sorts of health issues. However, familial natural short sleeper (FNSS) individuals sleep 4-6.5 hours a night most of their live and stay healthy. We set out to determine whether natural short sleep mutations can offer protection from various diseases. We chose Alzheimer as an example to start. (more…)
Author Interviews, Genetic Research, Heart Disease, Technology / 17.03.2022 Interview with: Ali Torkamani, Ph.D. Director of Genomics and Genome Informatics Scripps Research Translational Institute Professor, Integrative Structural and Computational Biology Scripps Research La Jolla, CA 92037  What is the background for this study?  Response: Prior research has shown that people with higher polygenic risk for coronary artery disease achieve greater risk reduction with statin or other lipid lowering therapy. In general, adherence to standard guidelines for lipid lowering therapy is low - about 30% of people who should be on lipid lowering therapy are, with no correlation to their genetic risk. We set out to see whether communicating personalized risk, including polygenic risk, for coronary artery disease would drive the adoption of lipid lowering therapy. (more…)
Author Interviews, Genetic Research, NEJM / 10.11.2021 Interview with: Professor Sir Mark Caulfield Professor of Clinical Pharmacology William Harvey Research Institute Queen Mary University of London What is the background for this study? Response: Rare diseases affect 6% of the population in western nations and there are approximately 10,000 different disorders and many remain without a genomic diagnosis after usual testing during their life time. In 2013 the UK Government launched the 100,000 Genomes Project and created Genomics England to investigate the role of whole genome sequencing in rare disease, cancer and infection. Whole genome sequencing gives the most comprehensive read out of the entire genome. To do this we partnered with the National Institute for Health Research (NIHR) BioResource and 9 hospitals across England1. Our New England Journal of Medicine paper published on the 11th November 2021 reports findings on the early rare disease participants who helped us pilot procedures and processes that would be used to enrol at scale across the NHS and revealed the potential benefits for rare disease1. (more…)
Author Interviews, Weight Research / 07.11.2021 Interview with: Neha Agrawal PhD Department of Physiology Development and Neuroscience University of Cambridge What is the background for this study? Response: Obesity levels are rising rapidly around the world and are a major risk factor for diseases such as Type 2 diabetes, cancers and recently, COVID-19. New strategies to understand obesity are thus needed to prevent and treat obesity and associated disease. Genetic studies in humans have shown that 40-70% of variation in body weight depends on our genes. Therefore, identifying genes linked to obesity and understanding their function can be a useful way to both understand how we gain weight and identify potential targets for weight loss therapy. However, human genetic obesity studies face significant limitations in identifying causal obesity genes and understanding their relationship to weight gain in human patients. The model system Drosophila melanogaster (Fruit flies) has provided vital insights into fundamental biology and human diseases for over a century. It is a powerful genetic model with well conserved metabolic pathways. Fruit flies also gain weight when fed a high-sugar or high-fat diet and develop heart disease and diabetes. We therefore decided to use fruit flies to identify novel obesity genes and their site of action in the body. (more…)
Author Interviews, Genetic Research, Parkinson's / 06.05.2021 Interview with: Clemens R. ScherzerClemens R. Scherzer, M.D. Center for Advanced Parkinson Research Harvard Medical School Brigham and Women’s Hospital Boston, MA What is the background for this study? Response: Parkinson's disease is the fastest growing brain disorder. The number of patients is projected to double to 14 million by 2040. The total cost of Parkinson's is $52 billion every year in the U.S. Yet, there are no medicines available to slow the disease. Current treatments temporarily alleviate symptoms, but do not address the underlying disease process, which continues to relentlessly progress. To begin to solve this puzzle, we searched the genome of 3,821 Parkinson's disease patients for genetic variants linked to rapid progression over time to dementia, which is a major determinant for a Parkinson's disease patient’s quality of life. These patients were deeply characterized in the International Genetics of Parkinson Disease Progression (IGPP) Consortium, a grass-roots, collaborative network of Parkinson’s investigators, with 31,578 longitudinal study visits over up to 12 years from disease onset.  (more…)
Author Interviews, Cancer Research, Gastrointestinal Disease, Genetic Research / 03.05.2021 Interview with: Judy H. Cho, MD, Dean of Translational Genetics Director of The Charles Bronfman Institute for Personalized Medicine Icahn School of Medicine at Mount Sinai What is the background for this study? Would you briefly describe Crohn's disease? Whom does it primarily affect? Response: Crohn’s disease is a chronic inflammatory intestinal disease, which affects ~3 million Americans a year. Its most typical age of onset ranges from 15-30 years, and many of those diagnosed also exhibit frequent abnormal healing and complications that constrict the digestive tract. The highest risk genetic mutations that increase risk for Crohn’s disease are found in the gene NOD2; these were first reported 20 years ago. Biological mechanisms by which NOD2 mutations drive Crohn’s disease, and especially fibrotic complications, have been incompletely described up until this point. Further, the reasons why many patients fail to respond to the commonly administered anti-TNF treatments also remain incompletely understood. (more…)
Author Interviews, Genetic Research, Ophthalmology, Science / 12.03.2021 Interview with: eye-eyecolor-geneticsDr Pirro Hysi Senior Lecturer in Ophthalmology Kings College London What is the background for this study? Response: - Iris (eye) color is an important human trait. It is one of the main features that makes our faces unique and recognizable. Iris color is similar to other pigmentatio traits, like hair and skin color, in that it is determined by the concentration and relative ratios of the melanin pigment. Pigmentation traits are roughly determined by several of the same genes regulating pigmentation, but many other genes seem to selectively determine pigmentation in any of these tissues. (more…)
AHA Journals, Author Interviews, Genetic Research, Heart Disease / 08.03.2021 Interview with: Giordano Bottà, PhD CEO and Co-founder Allelica The Polygenic Risk Score Company What is the background for this study? Response: Previous research identified that polygenic risk score (PRS) has the highest predictive power compared to other risk factors and identifies individuals with the same risk of those with familial hypercholesterolemia, but are invisible to traditional risk assessment. We explored for the first time the interplay between the main causes of atherosclerosis, LDL cholesterol and PRS.  We were interested in helping cardiologists understand why some individuals have bad arteries full of plaques while others don't in presence of the same LDL levels and no additional risk factors. Our findings explain why this is the case: LDL does not affect everyone the same. We believe that we are at the forefront of a change of paradigm in cardiovascular risk assessment: LDL levels cannot be accessed without considering the genetics of an individual. (more…)
Author Interviews, Genetic Research / 03.02.2021 Interview with: Igor Chesnokov, Ph.D Department of Biochemistry and Molecular Genetics School of Medicine University of Alabama at Birmingham, Alabama What is the background for this study? Response: DNA replication is fundamentally important for tissue development, growth and homeostasis. Impairments of the DNA replication machinery can have catastrophic consequences for genome stability and cell division. Meier-Gorlin Syndrome (MGS) is an autosomal recessive disorder that is also known as ear, patella, short stature syndrome and/or microtia, absent patella, micrognathia syndrome, traits highlighting the core clinical phenotypes. The genes affected by MGS mutations include many members of pre-replicative complex (pre-RC), such as Origin Recognition Complex (ORC) subunits (Orc1, Orc4, Orc6), Cdc6, Cdt1, CDC45, MCM5 as well as Geminin, suggesting that the clinical phenotype is caused by defects in DNA replication initiation. As the pre-RC complex is essential for DNA replication, the mutations in its components are expected to impair cell proliferation and reduce growth. The smallest subunit of ORC, Orc6, is the most divergent and enigmatic among ORC subunits. Orc6 is important for DNA replication in all species. Metazoan Orc6 proteins consist of two functional domains: a larger N-terminal domain important for binding of DNA and a smaller C-terminal domain important for protein-protein interactions. A mutation coding for a tyrosine 232 to serine alteration (Y232S) in the C-terminal domain of Orc6 is linked to MGS in humans. Recently, a new Orc6 mutation was described that also resulted in MGS. Unlike the previously described MGS mutation, this amino acid substitution, Lysine 23 to Glutamic acid (K23E), localizes in the N-terminal domain of Orc6.  (more…)
Author Interviews, Autism, Fertility, Genetic Research / 12.01.2021 Interview with: Michael Skinner,  PhD Eastlick Distinguished Professor Founding Director, Center for Reproductive Biology School of Biological Sciences Washington State University Pullman WA What is the background for this study? Response: Over twenty years ago we identified the existence of a non-genetic form of inheritance through analysis of environmentally induced epigenetic transgenerational inheritance of disease, now well established in a number of species including humans.  I was giving a talk on this topic at a meeting in Spain.   This study was initiated following the scientific meeting in Spain with an in vitro fertilization clinical group that said they had access to sperm from males with and without autistic children.  It took several years to collect and characterize the samples, and find financial support for the study.  Once this was done then we did the molecular analysis to see if the sperm from fathers with autistic children had epigenetic, DNA methylation alterations, that associated with them having offspring with autism. (more…)