Genetic Factors in Multifactorial Diseases PDF

Chapter 08 Genetic factors in multifactorial diseases Dra Verónica Veses Jiménez Chapter overview Definition of multifactorial disorders Methods to study multifactorial disorders Case studies 2  The contributions of genetic and env...

Chapter 08 Genetic factors in multifactorial diseases Dra Verónica Veses Jiménez Chapter overview Definition of multifactorial disorders Methods to study multifactorial disorders Case studies 2  The contributions of genetic and environmental factors to human diseases Haemophilia Peptic ulcer Osteogenesis imperfecta Diabetes Duchenne Club foot muscular dystrophy Pyloric stenosis Tuberculosis Dislocation of hip GENETIC ENVIRONMENTAL Spina bifida Scurvy Ischaemic heart disease Phenylketonuria Ankylosing spondylitis Galactosaemia Rare Common Genetics simple Genetics complex Unifactorial Multifactorial High recurrence rate Low recurrence rate 3 Multifactorial disorders Their inheritance is controlled by many genes with small additive effects (polygenic) plus the effects of the environment Because of that the proband is usually the only one affected in his/her family Clinical clue: usually one organ system affected 4 Characteristics of multifactorial disorders 1. The disease can occur in isolation, with affected children born to unaffected parents. Although familial aggregation is also common, there is no clear Mendelian pattern of inheritance. 2. Environmental influences can increase or decrease the risk of the disease. 3. The disease occurs more frequently in one gender than in the other, but it is not a sex-limited trait. 4. The concordance rates in identical and fraternal twins contradict Mendelian proportions. A concordance rate is a measure of the rate at which both sets of twins bear a specific disease. 5. The disease occurs more frequently in a specific ethnic group. 5 Common multifactorial diseases Congenital malformations Adult onset disorders Cleft lip/palate Diabetes mellitus Congenital hip dislocation Epilepsy Congenital heart defects Glaucoma Neural tube defects Hypertension Pyloric stenosis Ischaemic heart disease Club foot Manic depression Schizophrenia 6 METHODS TO STUDY MULTIFACTORIAL DISORDERS 7 How is evidence gathered for genetic factors in complex diseases? Because of the complex interactions between several genes and the environment, pedigree analysis used in Mendelian disorders cannot prove multifactorial disorders. The main approaches include: – twin concordance studies – family correlation studies – GWAS (Genome-wide association studies) 8 Twin studies What is the incidence in monozygotic (identical) compared with dizygotic (fraternal) twins? Monozygotic twins are genetically identical as they arise from a single zygote that divides into two embryos during the first 13 days of gestation Dizygotic twins result from two eggs fertilised by two spermatozoa, and therefore, on average, one-half of their genes are common, being genetically equivalent to brothers and sisters (siblings) 9 Determination of concordance Twins are concordant if they both show a discontinuous trait and discordant if only one shows the trait As twins usually share a similar family environment, it may be difficult to separate the genetic and environmental contributions to a multifactorial trait In this cases, studies with monozygotic twins reared apart can contribute greatly to the research in multifactorial disorders 10 Results of twin studies Monozygotic twins have identical genotype and dizygotic twins are like siblings (share 50% of the genes on average): – Conditions with no genetic component will have similar concordance rates in both types of twins – For monogenic or chromosomal disorders, the concordance in MZ twins will be 100% and in DZ twins less than this and equal to the rate in siblings 11 Twin studies: multifactorial disorders For multifactorial disorders, the concordance rate in MZ twins exceeds that in DZ twins, however, the concordance rate in MZ twins can range from 6 to 100% This range reflects the heritability of the condition: the higher the monozygotic concordance, the more important the genetic contribution, and so the higher the heritability 12  Twin concordance for some multifactorial disorders Disorder Monozygotic Dizygotic Cleft lip 35 5 Congenital 41 3 dislocation of hip epilepsy 37 10 hypertension 30 10 schizophrenia 45 12 13 Family correlation studies What is the incidence of a disorder in relatives compared with the incidence in the general population? Relatives share a proportion of their genes. Therefore, if a trait is determined by multifactorial inheritance, relatives should show the trait in proportion to their genetic similarity 14 Proportion of genes shared by relatives Degree of Examples Proportion of relationship genes in common First Parent to child, 50% sibling to sibling Second Grandparent to 25% grand child, nephew or niece to aunt or uncle Third First cousins 12.5% 15 Frequency of multifactorial disorders for different degrees of relationship Trait 1st degree 2nd degree 3rd degree Population frequency Cleft lip 4 0.6 0.3 0.1 Spina bifida 4 1.5 0.6 0.3 Schizophrenia 10 4 2 1 Epilepsy 5 2.5 1.5 1 16 Genome-wide association studies In GWAS, researchers compare variants across the entire genome in a case control study. It can be applied to any disease, independently of the inheritance pattern. This approach is hypothesis-free. No prior assumption is made about the genes likely to be involved in a disease. Results obtained so far have found hundreds of reproducible associations with more than 80 common diseases. Results are available at: http://www.genome.gov/gwastudies/ 17 Other studies in multifactorial disorders: focusing on environmental contribution Adoption studies: what is the incidence in adopted children of the disorders which their parent had? Population and Migration studies: what is the incidence in people from a particular ancestry group when they move to a different geographical area? 18 Basic concepts in multifactorial disorders Heritability – estimate of percentage of trait that is caused by genetics Correlation coefficient – proportion of genes two relatives share Concordance – Percentage of twin pairs that both show phenotype 19 MULTIFACTORIAL CONGENITAL DISEASES 20 Cleft lip and palate A cleft is a gap or split in the upper lip, the roof of the mouth (palate), or sometimes both. It occurs when separate areas of the face do not join together properly during pregnancy. 21 Cause of cleft lip/palate: combination of genetic and environmental factors Environmental factors (during Genetic factors pregnancy) More than 50 genes have Lack of folic acid been associated with Smoking different presentations Alcohol (cleft lip with or without Obesity palate; cleft palate…) Some teratogenic drugs 22 Neural tube defects Neural tube defect is a general term for a congenital malformation of the central nervous system occurring secondary to lack of closure of the neural tube during embryogenesis. The majority of cases can be categorized as either anencephaly (lack of closure in the region of the head) or spina bifida (lack of closure below the head) 23  Spina bifida Spina bifida is a condition where the spine does not develop properly, leaving a gap in the spine In most cases surgery can be carried out to close the opening in the spine. However, early damage to the nervous system can lead to problems such as: – weakness or total paralysis of the legs – bowel and urinary incontinence – hydrocephalus (excess fluid on the brain) 24 Cause of Spina bifida Genetic factors Environmental factors More than 200 genes have Lack of folic acid during the been implicated in neural first trimester of pregnancy tube defects in animal models To date no precise information available 25 Clubfoot: congenital talipes equinovarus Clubfoot is congenital deformity of the foot and ankle The foot of a baby with clubfoot points down and inwards, with the soles of the feet facing backwards 26 Cause of clubfoot: unknown The cause of clubfoot is unknown (idiopathic), although two genes, PITX1 and TBX4, have been recently associated It is not caused by the position of the fetus in the womb. In some cases, clubfoot can be associated with other congenital abnormalities of the skeleton, such as spina bifida Studies have strongly linked clubfoot to cigarette smoking during pregnancy 27 MULTIFACTORIAL ADULTHOOD DISEASES 28 Common diseases Diseases such as diabetes, cancer, cardiovascular and coronary artery disease, mental health, and neurodegenerative disorders are responsible for the majority of morbidity and mortality in developed countries frequency greater than 1 in 1000. 29 Genetic susceptibility A genetic susceptibility or predisposition is an increased likelihood of developing a particular disease based on a person’s genetic makeup. A genetic predisposition results from specific genetic variations that are often inherited from a parent. These genetic changes contribute to the development of a disease but do not directly cause it. 30 From genetic susceptibility to disease Some people with a predisposing genetic variation will never get the disease while others will, even within the same family. In people with a genetic predisposition, the risk of disease can depend on multiple factors in addition to an identified genetic change. These include other genetic factors (sometimes called modifiers) as well as lifestyle and environmental factors. 31 Main mechanisms of genetic susceptibility Single-gene inheritance of an abnormal gene product. Example: mutation in FH gene leads to familial hypercholesterolemia and early coronary artery disease. Inheritance of a single polymorphism. Example: acetaldehyde dehydrogenase activity and alcoholism. Inheritance of several single-gene polymorphisms. Example: antigens of the major histocompatibility complex and Diabetes Mellitus Type I. 32 Genetic susceptibility to infectious disease Additionally to the contribution of genetics to common diseases, recent genome-wide studies have reported novel associations between common polymorphisms and susceptibility to many major infectious diseases in humans 33 EXAMPLES OF GENETIC PREDISPOSITION 34 GWAS: The Wellcome Trust Case Control Consortium An initiative that combines 50 research groups throughout the UK. It is based on a large selection of cases and controls: 2,000 cases and 3,000 shared controls for 7 complex human diseases of major public health concern: Type II diabetes (T2D) Crohn’s disease (CD) Coronary artery disease (CAD) Rheumatoid arthritis (RA) Type I diabetes (T1D) Hypertension (HT) Bipolar disorder (BD) 35 Results: Genome-wide scan for seven diseases For each of seven diseases -log10 of the trend test P value for quality-control- positive SNPs, excluding those in each disease that were excluded for having poor clustering after visual inspection, are plotted against position on each chromosome 36 Focus on: Diabetes Mellitus Diabetes is a disease in which the body does not produce or properly use insulin. There are three major classes of diabetes: Type 1 diabetes: this results from an autoimmune reaction against the b-cells of the pancreatic islets, with onset between 10 to 13 years. Type 2 diabetes: this results from insulin resistance, combined with relative insulin deficiency. As a result of this the cells may be starved for energy and over time, high blood glucose levels may damage the eyes, kidneys, nerves or the heart. Gestational diabetes: this is a type of diabetes, that only pregnant women get. It is one of the top health concerns related to pregnancy. If not treated, gestational diabetes can cause problems for mothers and babies. 37 Diabetes Mellitus Type 1 Concordance rates in monozygotic twins are 50% and 12% in dizygotic twins. Therefore it can be concluded that there is genetic and environmental contributing factors to the disease. Environmental factors include: diet, viral exposure during early childhood and certain drugs. 38 Genetic factors in DMT1 Six genes/regions with strong statistical support for a role in T1D- susceptibility: – the major histocompatibility complex (MHC) – the genes encoding insulin – CTLA-4 (cytotoxic T-lymphocyte associated 4) – PTPN22 (protein tyrosine phosphatase, non-receptor type 22) – and the regions around the interleukin 2 receptor alpha (IL2RA/CD25) – interferon-induced helicase 1 genes (IFIH1/MDA5) Additionally GWAS have pointed out several novel regions (on chromosomes 12q13, 12q24, 16p13, 4q27, 12p13, 18p11 and the 10p15 CD25 region) associated with DMT1. 39 Diabetes Mellitus Type 2 The concordance rate in monozygotic twins is close to 100%, and 10 % in dizygotic twins and other first- degree relatives. Almost 20 loci have shown association with DMT2, and all of them show small relative effects (small odds ratios), indicating that the genetic component of the disease is formed by the combination of many gene variants, each having an small effect. 40 Genetic factors in DMT2 41  TFC7L2 is a transcription factor implicated in blood glucose homeostasis. PPARG encodes a member of the peroxisome proliferator- activated receptor (PPAR) subfamily of nuclear receptors. It is a regulator of adipocyte differentiation. Additionally it has been implicated in the pathology of numerous diseases including obesity, diabetes, atherosclerosis and cancer. KCNJ11 (Potassium Voltage-Gated Channel Subfamily J Member 11). It is associated with Diabetes Mellitus, Permanent Neonatal and Hyperinsulinemic Hypoglycemia, Familial, 2. 42 Genetic susceptibility to infectious disease Host genetic factors play a major role in determining differential susceptibility to major infectious diseases of humans, such as malaria, HIV/AIDS, tuberculosis, and invasive pneumococcal disease. Six of the genes that have a major effect on infectious disease susceptibility in humans have been identified in case-control studies Recent GWA studies have also identified susceptibility loci for chronic infections such as leprosy and chronic hepatitis B virus 43 Genetic variants with major effect on infectious disease susceptibility 44 GWAS and…. Leprosy: significant association between SNPs in the genes CCDC122, C13orf31, NOD2, TNFSF15, HLA-DR, and RIPK2 and a trend toward an association with a SNP in LRRK2 detected in a Chinese study. Hepatitis C: one of the interferon lambda genes, IL-28B, has shown association with viral clearance and with response to treatment HIV: human leukocyte antigen (HLA) class I variation, particularly HLA-B*5701 is associated with a protective effect in European population, whereas where HLA-B*5703 plays a major role in viral control in African-American populations. 45  GWAS and COVID Genetic data confirms that blood group O is associated with a lower risk of acquiring Covid-19 , whereas blood group A was associated with a higher risk. SLC6A20, encodes the sodium–proline transporter, which interacts with angiotensin-converting enzyme 2, the SARS-CoV-2 cell-surface receptor. CCR9 and CXCR6 are genes encoding chemokine receptors. 46 References Lobo, I. (2008) Multifactorial inheritance and genetic disease. Nature Education 1(1):5 http://www.genome.gov/gwastudies/ Dixon MJ, Marazita ML, Beaty TH, Murray JC. Cleft lip and palate: synthesizing genetic and environmental influences. Nature reviews Genetics. 2011;12(3):167-178. doi:10.1038/nrg2933. Dobbs MB, Gurnett CA. Genetics of Clubfoot. Journal of pediatric orthopaedics Part B. 2012;21(1):7-9. doi:10.1097/BPB.0b013e328349927 Au KS, Ashley-Koch A, Northrup H. Epidemiologic and genetic aspects of spina bifida and other neural tube defects. Developmental disabilities research reviews. 2010;16(1):6-15. doi:10.1002/ddrr.93. 47 References II Peter D Turnpenny , 2011. Emery's Elements of Medical Genetics. 14th Edition. Churchill Livingstone. Saunders Elsevier , 2007​. Edward S. Tobias, 2011. Essential Medical Genetics. 6th Edition. Wiley-Blackwell. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. The Wellcome Trust Case Control Consortium. Nature 447, 661-678(7 June 2007) doi:10.1038/nature05911 Hill AV. Evolution, revolution and heresy in the genetics of infectious disease susceptibility. Philos Trans R Soc Lond B Biol Sci. 2012; 19: 367(1590): 840–849. 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