PHAR 7322 Session 11 Genetic and Disease Susceptibility PDF

PHAR 7322: Introduction to Pharmacogenetics, Pharmacogenomics, and Personalized medicine Genetics and Disease Susceptibility Liang-Jun Yan, Ph.D.  Session learning objectives After completing this session, you should be able to:  Tell what constitutes...

PHAR 7322: Introduction to Pharmacogenetics, Pharmacogenomics, and Personalized medicine Genetics and Disease Susceptibility Liang-Jun Yan, Ph.D.  Session learning objectives After completing this session, you should be able to:  Tell what constitutes a complex disease.  Define heritability and how to interpret an estimate of heritability.  Describe the two primary models of complex human disease. Describe the opposing sides in the Common vs. Rare Variant debate.  Discuss the genotype-to-phenotype relationships that complicate genetic analyses.  Define epigenetics; describe DNA methylation and imprinting.  Session learning objectives After completing this session, you should be able to:  Tell what constitutes a complex disease.  Define heritability and how to interpret an estimate of heritability.  Describe the two primary models of complex human disease. Describe the opposing sides in the Common vs. Rare Variant debate.  Discuss the genotype-to-phenotype relationships that complicate genetic analyses.  Define epigenetics; describe DNA methylation and imprinting.  Genetics & Disease Susceptibility  Many diseases have an entirely genetic etiology (Mendelian)  Most (all?) diseases are impacted by genetic factors in either their risk, progression rate, or treatment approach/success  This is the basis and motivation for Personalized Medicine The goal of personalized medicine is to treat the individual, not the disease by using genetic and biological systems information.  The knowledge that is needed to implement personalized medicine is currently lacking for most diseases Complex Disease What is a complex disease? A complex disease would have many genes involved, often significant environmental contributions are also involved. It is not a simple Mendelian single- gene disorder  Complex Disease: Examples  Cancer  Cardiovascular disease  Hypertension  Alzheimer’s disease  Type two diabetes  Bipolar disease  Neural tube defects  Genetics and Disease Susceptibility  The role of genetics in complex disease is largely relegated to collection of family medical history Shared genetics AND environment raw estimate of overall risk  This does not mean that the HGP has failed, it simply illustrates the complexity of human disease (HGP: human genome project)  The HGP translated the book of life, we now have to study it thoroughly to understand the meaning of the text  It’s a relatively complicated task due to the things we will discuss; epistasis, low penetrance, small effect sizes, non- uniform environment  Complex Disease Etiology-The Threshold Concept Again, many genes involved, often Additive effects significant environmental contributions  The Complex of Disease risk GWAS: Genome-wide association studies The missing heritability problem is that variants discovered by GWAS only explain a minor fraction of the expected heritability. This maybe because: The effect sizes are much smaller than previously thought (GRR 1.1 rather than 2) We may have over-estimated the heritability in twin/pedigree studies It is rare variants, not common variants, that contribute to most of the variations Epigenetic inheritance accounts for much of the resemblance among  Session learning objectives After completing this session, you should be able to:  Tell what constitutes a complex disease.  Define heritability and how to interpret an estimate of heritability.  Describe the two primary models of complex human disease. Describe the opposing sides in the Common vs. Rare Variant debate.  Discuss the genotype-to-phenotype relationships that complicate genetic analyses.  Define epigenetics; describe DNA methylation and imprinting.  Heritabilit y …is the proportion of variance of a phenotype in a population that can be attributed to genotypic differences h2= VG/VP where VP= VG+ VE Where VG is the observed variance in genotypes of the population and VP is the variance of phenotypes in the population; VP can be due to both genetics (VG) and environment (VE). The phenotypes may be discrete, such as disease status; categorical, such as number of digits; or continuous, such as height or a biochemical measure.  Heritabilit y …is the proportion of variance of a phenotype in a population that can be attributed to genotypic differences h2= VG/VP where VP= VG+ VE The phenotypes may be discrete, such as disease status; categorical, such as number of digits; or continuous, such as height MZ: monozygotic or a biochemical measure. DZ: dizygotic Determine the difference! Strength of Estimatin g heritability: These Twinare hard to studies come by!! If intelligence is the same, it must be due to genetics If intelligence is different, it must be due to the environment  Heritabilit y …is the proportion of variance in a population that can be attributed to genotypic differences h2= VG/VP where VP= VG+ VE The phenotypes may be discrete, such as disease status; categorical, such as number of digits; or continuous, such as height or a biochemical measure. Some things to keep in mind-- 1. Heritability is not a statement about individuals. 2. Heritability is only a statement about a single population. 3. Heritability is not the same as inheritance. Inheritance is the correspondence between children and their biological parents. It can be due to environmental, including cultural, factors that are shared by family members. The only way to confidently interpret heritability is to actually measure the genotypic contribution.  Session learning objectives After completing this session, you should be able to:  Tell what constitutes a complex disease.  Define heritability and how to interpret an estimate of heritability.  Describe the two primary models of complex human disease. Describe the opposing sides in the Common vs. Rare Variant debate.  Discuss the genotype-to-phenotype relationships that complicate genetic analyses.  Define epigenetics; describe DNA methylation and imprinting.  Models of Complex Disease CDCV: Common Disease / Common Variant  The proposition that most disease susceptibility can be attributed to 10 to 20 specific loci, each of which explain around 5% of disease risk. (small effects of risk alleles with low penetrance)  Infinitesimal loci model (subset of CDCV) The proposition that we all carry thousands of very weak susceptibility alleles, and those unlucky enough to have too many are at highest risk, where rare variants or environmental triggers push them over the edge; implies a threshold RAME: Rare alleles of Major Effect  The proposition that diseases are highly heterogeneous, with hundreds or thousands of rare mutations causing individual cases of disease.  Arguments for/against common alleles FOR: AGAINST:  GWASs have successfully  The missing heritability has identified thousands of common not been accounted for in many variants. common diseases.  Model organism research  Demographic phenomena supports common variant suggest more than a simple contributions to complex common variant model. phenotypes.  Absence of blending  The infinitesimal model (see inheritance. next slide) is well validated in  Very few common variants for quantitative genetics. disease have been functionally  Common variants collectively validated. capture most of the genetic variance in GWASs (see next slide). Background: Infinitesimal Loci Model Thousands of very weak susceptibility alleles, and those unlucky enough to have too many are at highest risk, where rare variants or environmental triggers push them over the edge; implies a threshold The longer the chromosomes, the higher the variance  Arguments for/against rare alleles FOR: AGAINST:  Evolutionary theory predicts  Sibling recurrence rates that disease alleles should be are greater than the rare. postulated effect sizes of rare  Empirical population genetic variants. data show that deleterious  Genome-wide associations variants are rare. are consistent across  Rare copy number variants populations. contribute to several complex  Epidemiological psychological disorders. transitions cannot be  Many rare familial disorders attributed to rare variants. are due to rare alleles of large  Rare variants do not have effect. Rare alleles obviously major effects may explain the missing heritability found in genomeadditive effects. wide association studies (GWAS).  What each model would look like in a GWAS Manhattan plot… 10-20 loci, 5% contribution from each An infinitely large number of loci, each of which has the same infinitesimally small impact Greg Gibson Nature Reviews Genetics13,135-145(February 2012) doi:10.1038/nrg3118 Diseases are highly heterogeneous, with hundreds or thousands of rare mutations causing individual cases of disease  Common vs. Rare Variants  The debate over whether the CDCV or the RAME hypothesis is correct is far from resolved.  Whole genome sequencing has become cheap enough to allow this question to be addressed and answered  The answer is likely to be “YES” both hypotheses are correct, depending upon the disease and population  The discovery of complex disease genes and resolution of the underlying genetics of complex disease is one of the greatest current challenges to medical research  Session learning objectives After completing this session, you should be able to:  Tell what constitutes a complex disease.  Define heritability and how to interpret an estimate of heritability.  Describe the two primary models of complex human disease. Describe the opposing sides in the Common vs. Rare Variant debate.  Discuss the genotype-to-phenotype relationships that complicate genetic analyses.  Define epigenetics; describe DNA methylation and imprinting.  Genotype -> Phenotype…not always Mendelian Types of relationships between genotype and phenotype:  Allelic heterogeneity-  Locus heterogeneity-  Modifier genes-  Pleiotropy-  Penetrance/expressivity-  Genotype -> Phenotype…not always Mendelian Types of relationships between genotype and phenotype  Allelic heterogeneity-different mutations in the same gene cause the same phenotypic manifestations  Locus heterogeneity-mutations in several different genes or chromosomal loci cause a single phenotype  Modifier genes-genes that influence the expression of other genes and/or the phenotypic manifestation of a mutation; aka epistasis  Pleiotropy-one gene causes multiple phenotypes, usually due to being important in more than one path and/or more than one tissue type  Penetrance/expressivity-varying proportion of phenotype observed given a particular genotype.  Name that genotype-phenotype relationship: Familial Breast BRCA1 Cancer  Hypothetical population of 1 million Ashkenazi Jewish women followed from age 20 to age 70. (Taken from McClain et al, 2005, Genetics in Medicine) Allelic heterogeneity  66% of women who carry BRCA1 mutation develop breast cancer by age 55.  Name that genotype- phenotype relationship: Retinitis Pigmentosa Mutations in 45+ Locus heterogeneity genes yield the RP phenotype Retinitis pigmentosa Hartong, DyonneT et al. The Lancet , Volume 368 , Issue 9549 , 1795 -1809  Name that genotype- phenotype relationship: Phenylketonuria Allelic heterogeneity More than 400 mutations in the gene for phenylalanine hydroxylase (PAH) have been identified as causal of the PKU phenotype Lee, et al. Mutation analysis of PAH gene and characterization of a recurrent deletion mutation in Korean patients with phenylketonuria. Experimental & Molecular Medicine(2008)40,533- 540.  Name that genotype- phenotype relationship: Cystic Fibrosis Variants in genes that alter CF severity Allelic heterogeneity (impacted by gene modifiers or epistasis Cutting, Garry R. “Modifier Genes in Mendelian Disorders: The Example of Cystic Fibrosis.” Annals of the New York Academy of Sciences1214 (2010): 57–69.PMC. Web. 14 Oct. 2016.  A couple notes:  We discussed largely Mendelian disorders here to illustrate the concepts; these complexities of genetic interactions occur in the background of complex disease as well.  Many disorders may exhibit multiple G-> P relationships Ex: Cystic Fibrosis has genetic modifiers and is a great example of allelic heterogeneity. So this disease has both allelic heterogeneity and epistasis.  Session learning objectives After completing this session, you should be able to:  Tell what constitutes a complex disease.  Define heritability and how to interpret an estimate of heritability.  Describe the two primary models of complex human disease. Describe the opposing sides in the Common vs. Rare Variant debate.  Discuss the genotype-to-phenotype relationships that complicate genetic analyses.  Define epigenetics; describe DNA methylation and imprinting.  Epigenetic Mechanisms  Jean Baptiste Lamarck was a French biologist and a contemporary of Darwin  He theorized that acquired characters drive evolution  Epigenetics-histone modifications  Study of heritable changes that do not affect the DNA sequence  Negatively charged DNA is wrapped on positively charged histones Histone acetylation–decreases the positive charge of histone and decreases attraction to DNA->increases expression Histone methylation-tightens DNA coil around histone and self->decreases expression There are other types of epigenetic mechanisms, including non-coding RNA based regulation. Epigenetic Mechanisms-DNA Methylation  Epigenetic Mechanisms- Methylation  Methylation of DNA impacts gene expression  The environment can alter DNA methylation patterns  Methylation status drives gene expression and may be an important disease mechanism  Methylation patterns can be inherited  Imprintin g  Methylation of specific genes is heritable, and impacts which copy of the gene is expressed Only select genes are imprinted (1%) Generally those involved in growth and development  Prevents complementation! Any mutation in the expressed gene will result in phenotype Genomic imprinting is a form of epigenetic inheritance whereby the regulation of a gene or chromosomal region is dependent on the sex of the transmitting parent. During gametogenesis, imprinted regions of DNA are differentially marked in accordance to the sex of the parent, resulting in parent-specific expression (If a gene is suppressed through imprinting from one parent, and the allele from the other parent is not expressed because of mutation neither can act and the child will be deficient, leading to a disease phenotype)