Explore disease mechanisms and genetic analysis in this comprehensive lecture covering genome-wide association studies (GWAS), biological insights, and complex trait analysis. Learn about Bayesian fine-mapping, sub-threshold region prioritization, and tissue-specific component partitioning. Dive deep into the FTO locus, examining its connection to obesity through a six-step analysis process that includes tissue identification, target gene establishment, and phenotypic consequences. Master concepts like quantitative trait loci analysis, mediation analysis, Mendelian randomization, and heritability in systems genetics. Understand the differences between omnigenic, polygenic, and monogenic inheritance patterns while exploring how functional annotations contribute to heritability partitioning. Access supplementary materials including detailed notes, slides, and chapter resources to enhance learning of these complex genetic concepts.
Disease Mechanism and Genetic Analysis: From GWAS to Biological Insights - Lecture 18
Overview
Syllabus
Lecture Overview
Review: Genetics, Variation, GWAS, Polygenic scores PGS
From GWAS to biological insights
Bayesian Fine-Mapping
Sub-threshold Region Prioritization
GWAS locus dissection: enriched tissues, driver SNPs, target genes
Partitioning complex traits into tissue-specific components
From Individual GWAS Region to Mechanism and Circuitry
Introduction to FTO locus, strongest Genetic Association with Obesity
Step 1 - Establish relevant tissue/cell type
Step 2 - Establish downstream target genes
Step 3 - Establishing causal nucleotide variant
Step 4 - Establish upstream regulator causality
Step 5 - Establish cellular phenotypic consequences
Step 6 - Establish organismal phenotypic consequences
Quantitative Trait Loci: eQTL/meQTLanalysis
Mediation Analysis + Mendelian Randomization
Heritability and Systems Genetics
Partitioning heritability by functional annotations
Omnigenic vs. polygenic vs. monogenic inheritance
Summary
Taught by
Manolis Kellis
