Genetics for EpidemiologistsLecture 4: Genetic Association Studies

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Genetics for Epidemiologists Lecture 4: Genetic Association StudiesNational Human Genome Research InstituteNational Institutes of HealthU.S. Department of Health and Human ServicesU.S. Department of Health and Human Services National Institutes of Health National Human Genome Research InstituteTeri A. Manolio, M.D., Ph.D. Director, Office of Population Genomics and Senior Advisor to the Director, NHGRI, for Population Genomics

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Topics to be CoveredCase-control and cohort studies in genomic research Candidate gene studies Genome-wide association studies Randomized/experimental designs

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Collins FS, Nature 2004; 429:475-77.

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Desirable Characteristics of Large US Cohort StudyLarge sample size Full representation of US minority groups Broad range of ages Broad range of genetic backgrounds and environmental exposures Family-based recruitment for at least part of cohort to control for population stratification Broad array of clinical and laboratory data, regular follow up for events, additional exposure assessmentAfter Collins FS, Nature 2004; 429:475-77.

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Desirable Characteristics of Large US Cohort Study (continued)Technologically advanced dietary, lifestyle, and environmental exposure data Collection and storage of biological specimens Sophisticated data management system Broad access to materials and data Goals should not be “hypothesis-limited” Comprehensive community engagement from the outset State of the art (?dynamic) consent to allow multiple uses of data and regular feedbackAfter Collins FS, Nature 2004; 429:475-77.

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Larson, G. The Complete Far Side. 2003.

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Manolio TA et al. Nature 2006; 7:812-820.

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Willett WC et al. Nature 2007; 445:257-258.

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Collins FS et al. Nature 2007; 445:259.

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Pros and Cons of Case-Control StudiesAdvantages May be the only way to study rare diseases or those of long latency Existing records can occasionally be used if risk factor data collected independent of disease status Can study multiple etiologic factors simultaneously May be less time-consuming and expensive If assumptions met, inferences are reliable

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Pros and Cons of Case-Control StudiesDisadvantages Relies on recall or records for information on past exposures; validation can be difficult or impossible Selection of appropriate comparison group may be difficult Multiple biases may give spurious evidence of association between risk factor and disease Usually cannot study rare exposures Temporal relationship between exposure and disease can be difficult to determine

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“But,” they say, “This Is Genetics!” (you dumb epidemiologist) “This Is Different!”Genes are measured the same way in cases and controls Information on key exposure is easy to validate No recall or reporting involved Temporal relationship between genes and disease is piece of cake “BUT,” I SAY, Bias-free ascertainment of cases and controls is still major concern; cases in most clinical series unlikely to be representative Assessment of risk modifiers or gene-environment interactions is likely to be incomplete or flawed

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Appreciation of Weaknesses of Case-Control Studieshttp://www.mainlesson.com/display.php3?author=treadwell&book=primer&story=chickenlittleLarson, G. The Complete Far Side. 2003.

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Candidate Genes

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Genetic Studies in Unrelated Individuals (pre-2005): Candidate Gene StudiesGoal: characterize candidate genes and variants related to disease Not typically intended to “find genes,” generally begun after disease-related variants identified Assess generalizability of family-based observations (genetic heterogeneity) Assess importance of allelic variation at population level (PAR, penetrance) Identify modification of genetic association by environmental factors (GxE interaction)

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Population Studies of Genetic Variants: Angiotensin I-Converting Enzyme (ACE)Larsen: Williams Textbook of Endocrinology, 10th ed., 2003

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ACE Gene IdentificationcDNA sequence determined for human testicular ACE, identical from residue 27 to C terminus to C-terminal domain of endothelial ACE (Ehlers et al, PNAS 1989) Assigned to chromosome 17q23 by in situ hybridization (Mattei et al, Cytogenet Cell Genet 1989) Linked to elevated blood pressure in rat model of hypertension (Jacob et al, Cell 1991) Mapped to human chromosome 17q22-q24 (Jeunemaitre et al, Nat Genet 1992)

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ACE Gene PolymorphismsInsertion/deletion polymorphism identified through restriction fragment length polymorphism (RFLP) analysis Two alleles results from 250-bp insertion in intron 16; allele frequencies = 0.41 for I allele and 0.59 for D allele Accounted for 47% variance in serum ACE in 80 subjectsRigat et al, J Clin Invest 1990; 86:1343-46.

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Nature 1992; 359:641-44.

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Cambien et al, Nature 1992; 359:641-44.Frequency of ACE Genotypes in 1,304 MI Cases and ControlsOR = 1.34, p = 0.007197200309390104104

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Cambien et al, Nature 1992; 359:641-44.Frequency of ACE Genotypes in 1,304 MI Cases and ControlsOR = 3.2 [1.7,5.9]384641143159 154372 390OR = 1.1 [0.9,1.5]Low RiskHigh Risk

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Age-Adjusted Odds on Hypertension by ACE ID/DD Genotype and Sexafter O’Donnell C et al, Circulation 1998; 97:1766-72.

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Number of New, Significant Gene-Disease Associations by Year, 1984 - 2000 Hirschhorn J et al, Genet Med 2002; 4:45-61.

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Of 600 Gene-Disease Associations, Only 6 Significant in > 75% of Identified StudiesHirschhorn J et al, Genet Med 2002; 4:45-61.Hirschhorn J et al, Genet Med 2002; 4:45-61.

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Reports For and Against Associations of Variants with Carotid Atherosclerosis Manolio et al, ATVB 2004; 24:1567-1577.

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Summary Points: Candidate Gene Studies Initial enthusiasm markedly damped by failure to replicate Can probably find study or story that will fit almost any candidate to any disease/trait Understanding of genome structure and function, and of pathophysiologic mechanisms, just too preliminary to project more than a handful of plausible candidates at present

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Last Updated: 8th March 2018

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