An Sci 362 1st Edition Lecture 22 Outline of Last Lecture I. General DefinitionsII. Melanin Sythesisa. MC1RIII. Important Conceptsa. 1b. 2i. Tyrosineii. Agoutic. 3i. K Locus, B-DefensinIV. Spotting LocusOutline of Current Lecture I. ReadingII. Whole Genome Association StudyIII. Linkage Disequilibrium AnalysisIV. WTCCCa. Objectivesb. Populationc. Control Groupsd. Crohn’s DiseaseV. LessonsCurrent LectureReading Assignment- OR: Odds Ratioo Ratio of odds of being affected with disease given certain genotypes at a SNP locus- Relative risk is another measureWhole Genome Association Study- Samples drawn from general populationo Avoiding stratification- Phenotypes with discrete classes (ie. disease)These notes represent a detailed interpretation of the professor’s lecture. GradeBuddy is best used as a supplement to your own notes, not as a substitute.o Case (affected) versus control (unaffected)- Phenotypes for continuous traitso Sample from tails of the distributionLinkage Disequilibrium Analysis- Genotype LARGE number of SNPs- Test association between phenotype and marker genotypeo Do SNP allele frequencies differ between case and control groups?- Association between gene and linked markers diminished for all but the most closely linked markers due to accumulated recombination events- Human genotypingo Current tools ~ 1 million SNPs typed per sampleo (~1 SNP every 3,000 bp)- Animal genotyping (cow, pig, horse, chicken, dog)o Current tools ~ 50-60,000 SNPs typed per sampleo (~1 SNP every 50,000 bp)o High density chips (800k) available in some speciesWho is the WTCCC- Objectiveso Conduct a whole-genome association (WGA) study of large scale for: Bipolar disorder Coronary artery disease Crohn’s disease Rheumatoid arthritis Type 1 diabetes Type 2 diabeteso Improve efficiency of design by shared control groupo Develop tools for analysis of WGA studies- Population Studiedo Residents of UK from England, Scotland and Wales Self-identified as white European Controls: 1500 from 1958 British Birth Cohort and 1500 from blood donors 17,000->9377->7692->1500 3622->1564 Balanced representation of gender and location- Why 2 control groups?o Assess bias in obtaining control sampleso Check for differences related to method of sample collection and DNA preparation- Crohn’s Disease Phenotypeo Attendees at inflammatory bowel disease clinics at Cambridge, Oxford, London, Newcastle, & Edinburgh o Confirmed diagnosis of Crohn’s disease (CD) using conventional endoscopic, radiological and histopathological criteriao Included all subtypes of CD o Not specifically enriched for family history or early age of onseto Median age of diagnosis was 26.1 yr and 62% of the collection had undergone CD-related abdominal surgeryLessons Learned- Large sample size critical- Account for multiple statistical tests- Replication of results is essential- Comprehensive genomic coverage important- SNP associations applicable across breeds
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