Multifactorial Inheritance

Abstract: A key public health need is to identify individuals at high risk for a given disease to enable enhanced screening or preventive therapies. Because most common diseases have a genetic component, one important approach is to stratify individuals based on inherited DNA variation1. Proposed clinical applications have largely focused on finding carriers of rare monogenic mutations at several-fold increased risk. Although most disease risk is polygenic in nature2-5, it has not yet been possible to use polygenic predictors to identify individuals at risk comparable to monogenic mutations. Here, we develop and validate genome-wide polygenic scores for five common diseases. The approach identifies 8.0, 6.1, 3.5, 3.2, and 1.5% of the population at greater than threefold increased risk for coronary artery disease, atrial fibrillation, type 2 diabetes, inflammatory bowel disease, and breast cancer, respectively. For coronary artery disease, this prevalence is 20-fold higher than the carrier frequency of rare monogenic mutations conferring comparable risk6. We propose that it is time to contemplate the inclusion of polygenic risk prediction in clinical care, and discuss relevant issues.

Abstract: A historical tendency to use European ancestry samples hinders medical genetics research, including the use of polygenic scores, which are individual-level metrics of genetic risk. We analyze the first decade of polygenic scoring studies (2008–2017, inclusive), and find that 67% of studies included exclusively European ancestry participants and another 19% included only East Asian ancestry participants. Only 3.8% of studies were among cohorts of African, Hispanic, or Indigenous peoples. We find that predictive performance of European ancestry-derived polygenic scores is lower in non-European ancestry samples (e.g. African ancestry samples: t = −5.97, df = 24, p = 3.7 × 10−6), and we demonstrate the effects of methodological choices in polygenic score distributions for worldwide populations. These findings highlight the need for improved treatment of linkage disequilibrium and variant frequencies when applying polygenic scoring to cohorts of non-European ancestry, and bolster the rationale for large-scale GWAS in diverse human populations. Predominant participation of European-ancestry individuals in genetic studies has hindered the better understanding of genetic risk in non-European ancestry individuals. Here, Duncan et al. quantify polygenic risk score use and performance in worldwide populations.

Abstract: VOLUME 1 PART 1 BASIC PRINCIPLES: History of Medical Genetics. Nature and Frequency of Genetic Disease. Gene Structure and Function. Mutations in Human Diseases: Nature and Consequences . Molecular Methodology. Mendelian Inheritance. Segregation Analysis. Analysis of Genetic Linkage. Genomics. Morbid Anatomy of the Human Genome. Chromosomal Basis of Inheritance. Cytogenetic Analysis. Mitochondrial Genetics. Multifactorial Inheritance and Genetic Analysis of Multifactorial Disease. Population Genetics. Pathogenesis of Genetic Disease. Genetic Epidemiology. Human Malformations. Twins and Twinning. The Molecular Biology of Cancer. The Biologic Basis of Ageing: Implications for Medical Genetics. Pharmacogenetics. The Human Major Histocompatibility Complex and Disease Susceptibility. PART II CLINICAL APPLICATIONS: GENERAL PRINCIPLES: Genetic Assessment and Pedigree Analysis. Risk Estimation in Genetic Counseling. Carrier Screening. Prenatal Screening for Neural Tube Defects and Down Syndrome. Prenatal Diagnosis. Neonatal Screening. Genetic Counseling. Strategies for the Treatment of Genetic Disease. Ethical Aspects of Genetic Screening and Diagnosis. Legal Issues in Genetics. APPROACHES to COMMON CLINICAL PROBLEMS: Infertility. Fetal Loss. A Clinical Approach to the Dysmorphic Child. Human Teratology. Abnormal Mental Development. Abnormal Body Size and Proportion. Transplantation Genetics. APPROACHES to SPECIFIC DISORDERS:: Cardiovascular Disorders: Congenital Heart Disease. Common Generic Determinants of Coagulation and Fibrinolysis. Cardiomyopathies. Familial Dysrhythmias. Molecular Genetics of Hypertension. Pre-Eclampsia. Chromosome Disorders: Down Syndrome and Other Autosomal Trisomies. Sex Chromosome Abnormalities. Deletions and Other Structural Abnormalities of the Autosomes. Connective Tissue Disorders: Marfan Syndrome and Other Disorders of Fibrillin. Ehlers-Danlos Syndrome. Pseudoxanthoma Elasticu M, Cutix Laxa, And Other Disorders of Elastic Tissue. Craniofacial Disorders: Craniofacial Disorders. Deafn

Abstract: Autism spectrum disorder (ASD) risk is influenced by common polygenic and de novo variation We aimed to clarify the influence of polygenic risk for ASD and to identify subgroups of ASD cases, including those with strongly acting de novo variants, in which polygenic risk is relevant Using a novel approach called the polygenic transmission disequilibrium test and data from 6,454 families with a child with ASD, we show that polygenic risk for ASD, schizophrenia, and greater educational attainment is over-transmitted to children with ASD These findings hold independent of proband IQ We find that polygenic variation contributes additively to risk in ASD cases who carry a strongly acting de novo variant Lastly, we show that elements of polygenic risk are independent and differ in their relationship with phenotype These results confirm that the genetic influences on ASD are additive and suggest that they create risk through at least partially distinct etiologic pathways