EPI507 Genetic Epidemiology Syllabus Fall 2011

EPI507 – Genetic Epidemiology – Syllabus – Fall 2016

Kresge G2 – Mondays and Wednesdays 10:30-12:20

Instructors and Office Hours

Peter Kraft, Professor of Epidemiology and Biostatistics

Office Hours: Building 2 Room 249
Mondays 12:30-1:30 and by appointment

Simin Liu, Professor of Epidemiology and Medicine, Brown University

Office Hours: By appointment

Dan Chasman, Associate Professor of Medicine, Harvard Medical School

Office Hours: By appointment

Teaching Assistants and Office Hours

Zhaozhong Zhu

Office Hours:Building 2 Room 247

Fridays, 9:00-10:00

Maxine Chen

Office Hours: Building 2 Room 247

Thursdays, 10:00-11:00

Anne Feng

Office Hours:Building 2 Room 247

Tuesdays, 12:30-2:00

Website

Readings

Required and suggested readings are listed in the course outline. Readings marked with an asterisk will be available in a hard-copy coursepack; all others will be available through the Countway library.

Readings should be completed by the Friday prior to the lecture where they will be discussed--for example, the required readings for the week of October 31st should be completed by October 28th. The online quizzes (due the Sunday beforethe material will be covered) will reference this material.

Textbook

Nan M. Laird and Christoph Lange. The Fundamentals of Modern Statistical Genetics. Springer: New York 2011. ISBN-10: 1441973370. Available electronically through Countway Library (go to Countway Library, click on books, search for "The Fundamentals of Modern Statistical Genetics").

Course Pack

Course pack readings are denoted with an ‘*’ in the detailed outline.

Angier N. Some Genetic Pieces Are Falling Into Place In Breast Cancer Puzzle. The New York Times 1990; 38. Available at:
Angier N. Fierce Competition Marked Fervid Race for Cancer Gene. The New York Times 1994; September 20:1. Available at:
Brice, P and Zimmern, R. The public health genomics enterprise. In: Muin J. Khoury SRB, Marta Gwinn, Julian P.T. Higgins, John P.A. Ioannidis, Julian Little, ed. Human Genome Epidemiology. 2nd ed. Oxford: Oxford University Press; 2010:36-62.
Kraft, P and Chen, J. Haplotype Association Analysis. In: Timothy R. Rebbeck CBA, Peter G. Shields, ed. Molecular Epidemiology: Informa healthcare USA; 2008:205-215
Lewontin R. Human Diversity: Scientific America Library; 1995.
Leutwyler K. Deciphering the breast cancer gene. Experts grapple with the implications of the finding. Sci Am. Dec 1994;271(6):26-28.
Thomas, DC. Basic Concepts of Molecular Genetics. Statistical Methods in Genetic Epidemiology: Oxford Univeristy Press; 2004:25-43.

Online Quizzes

An online quiz will be published every Wednesday, to be completed by Sundaymidnight to allow summary of quizzes answers before the lecture on Monday. These quizzes will cover material from the readings for material covered during the week starting on Monday. These quizzes will be graded on a "Showing up is 100% of the grade" basis: if you complete them (doesn't matter how well you do), you get 100%.

Homework

Weekly homeworks will be assigned on Wednesday, due the following Wednesday.

Forum for Discussion and Q&A for Homework

An online forum is available after log in the course site. Any topics related to the course can be discussed. One TA will be in charge of coordinating discussion but everyone is encouraged to actively contribute to discussion.

Grading

Online Quizzes:15%
Weekly homework:35%
In-class mid-term:20%
In-class final:30%

Homework and readings should require between 3 and 6 hours outside of class every week. Homework and exams will be cumulative and cover material from the readings and lectures.

Course Goals

At the end of the course, student will be able to:

describe how molecular, Mendelian, and population genetics relate to epidemiology;
describe the strengths and weaknesses of different study designs for understanding the relationship between genetic variation and variation in human traits;
describe and conduct analyses appropriate for different genetic association study designs;
relate concepts from genetic epidemiology to general epidemiologic concepts (e.g. population stratification bias is an example of confounding).

Students should be able to critically evaluate published genetic and epigenetic association studies and understand the strengths and limitations of particular studies and genetic epidemiology generally. They will also have a solid foundation for further study in genetic epidemiology and statistical genetics, should they choose to pursue this.

Tentative Outline

Subtopics and readings may change!

**UPDATED 10/26 (See Highlighted Section)**

Lecture 1. October 24. Introduction and basic molecular genetics.PK

Review syllabus and take pre-quiz [not for grade].
Genetic epidemiology as epidemiology.
Clinical and public health uses of genetics.
The central dogmaof molecular genetics.
The structure of DNA.
The genetic code: transcription and translation.
Genetic variation and its relationship to variation in human traits.

Required readings:

Laird and Lange (2011) pp. 1-13 (Chp. 1); Glossary #1&2.

Suggested readings:

Coursepack: Brice and Zimmern (2010)*; Angier (1990)*; Angier (1994)*; Leutwyler (1994)*; Thomas (2004), pp.25-43*.

Chanock SJ. Principles of High-Quality Genotyping. In: Timothy R. Rebbeck CBA, Peter G. Shields, ed. Molecular Epidemiology-Apllications in Cancer and Other Human Diseases: InformaHealthcare USA; 2008:63-80.

Pauling L, Itano HA, et al. Sickle cell anemia a molecular disease. Science. Nov 25 1949;110(2865):543-548.

Ingram VM. Gene mutations in human haemoglobin: the chemical difference between normal and sickle cell haemoglobin. Nature. Aug 17 1957;180(4581):326-328.

Allison AC. Protection afforded by sickle-cell trait against subtertianmalarial infection. Br Med J. Feb 6 1954;1(4857):290-294.

Suggested viewing:

Lecture 2. October 26. From molecular genetics to Mendelian genetics to genetic epidemiology. PK&SL

DNA replication and transmission to offspring.
Crossovers and recombination.
Mendel's laws of segregation and independent assortment.
Simple Mendelian traits.
Patterns of Mendelian inheritance.
Familial aggregation, segregation analyses, and sibling relative risks.

Required readings:

Laird and Lange pp. 15-28 (Chp. 2); Glossary#3.

Suggested readings:

Garrod AE. About Alkaptonuria.Med Chir Trans. 1902;85:69-78.

Suggested viewing:

Lecture 3. October 31. Genotypes and alleles.PK

Genotype frequencies, allele frequencies, and Hardy-Weinberg equilibrium
Testing for departure from Hardy-Weinberg equilibrium
Variation in genotype and allele frequencies in space and time

Required readings:

Laird and Lange pp. 15-28 (Chp. 2); Glossary#3.
Coursepack: Lewontin (1995), pp. 29-42*; 113-123*.

For in class discussion (choose ONE in coordination with your reading group):

Rosenberg NA, Pritchard JK, Weber JL, et al. Genetic structure of human populations. Science. Dec 20 2002;298(5602):2381-2385.
Fumagalli M, Moltke I, Grarup N et al. Greenlandic Inuit show genetic signatures of diet and climate adaptation. Science. 2015 Sep 18;349(6254):1343-7.
Li, Jun Z.; Absher, Devin M.; Tang, Hua; et al.Worldwide human relationships inferred from genome-wide patterns of variation. 2008;SCIENCE 319(5866) Pages: 1100-1104
Sabeti, Pardis C.; Varilly, Patrick; Fry, Ben; et al.Genome-wide detection and characterization of positive selection in human populations. 2007;NATURE 449(7164) Pages: 913-U12

Lecture 4. November 2.Linkage disequilibrium.DC&PK

Haplotypes.
Definition and measures of linkage disequilibrium.
Patterns of linkage disequilibrium within and across populations.
Uses of linkage disequilibrium: tagging and imputation.

Required reading:

Laird and Lange, pp. 77-79 (Chp. 5.4), 81-82 (Chp. 5.5); Glossary #4.

Need AC, Goldstein DB. Genome-wide tagging for everyone. Nat Genet. Nov 2006;38(11):1227-1228.

Suggested reading:

Gabriel SB,Schaffner SF, et al. The structure of haplotype blocks in the human genome. Science. 2002 Jun 21;296(5576):2225-9

Lecture 5. November 7.Genetic association studies.DC

Design of candidate gene studies: choosing “tagging SNPs.”
Design and analysis of population-based association studies.
Design and analysis of family-based association studies.
Comparison: population-based and family-based studies.

Required reading:

Lange and Laird, pp. 99-111 (Chp. 7 Intro – 7.6), 125-127 (Chp. 8 Intro)

Coursepack: Kraft and Chen (2008) 205-215*, 219-221*

Manolio TA, Bailey-Wilson JE, Collins FS. Genes, environment and the value of prospective cohort studies. Nat Rev Genet. Oct 2006;7(10):812-820.

Lecture 6. November 9. Population stratification bias.PK

Population stratification bias.
Genomic diversity.
Implications for genetic epidemiology design, analysis and interpretation.

Required reading:

Lange and Laird, pp. 161-164 (Chp. 10 Intro – 10.1.1)

Race, Ethnicity, and Ancestry Working Group. The use of racial, ethnic, and ancestral categories in human genetics research. Am J Hum Genet. Oct 2005;77(4):519-532.

Price AL, Zaitlen NA, et al. New approaches to population stratification in genome-wide association studies.Nat Rev Genet. Jul 2010;11(7):459-463.

Suggested viewing:

Lecture 7. November 14. Genome-wide association studies I.PK

Genome-wide genotyping panels: strengths and limitations.
The multiple testing problem.
Replication in principle and in practice.
Power, sample size, and meta-analysis.
Examples: breast cancer, height, smoking behavior.
"Missing heritability" and common criticisms of genome-wide association studies.

Required reading:

Pearson TA, Manolio TA. How to interpret a genome-wide association study.JAMA. Mar 19 2008;299(11):1335-1344.

Ioannidis JP. Why most published research findings are false. PLoS Med. Aug 2005;2(8):e124

Suggested reading:

Lange and Laird, pp. 175-185 (Chp. 11 Intro – 11.4); 186-189 (Chp. 11.5).

Lehrer J. The truth wears off. Dec 2010; Accessed Sept 19, 2016.

Suggested viewing:

Lecture 8. November 16.Genome-wide association studies II.TAs

For in class discussion:

TBD [PK]

Midterm. November 21.

No class. November 23.

Lecture 9. November 28.Rare variantsI.SL

Linkage studies (high penetrance mutation, BRCA example)
Design – why seq? Functional vs. others (target, exome, WGS)
Region selection

Required reading:

Lander ES. Initial impact of the sequencing of the human genome. Nature. Feb 10 2011;470(7333):187-197.

Kiezun A, Garimella K, Do R, et al. Exome sequencing and the genetic basis of complex traits. Nat Genet. Jun 2012;44(6):623-630.

Suggested reading:

The 1000 Genomes Project Consortium. A map of human genome variation from population-scale sequencing. Nature. Oct 28 2010;467(7319):1061-1073.

Nekrutenko A, Taylor J. Next-generation sequencing data interpretation: enhancing reproducibility and accessibility. Nat Rev Genet. Aug 17 2012;13(9):667-672.

Nielsen R, Paul JS, Albrechtsen A, Song YS.Genotype and SNP calling from next-generation sequencing data. Nat Rev Genet. Jun 2011;12(6):443-451.

Lecture 10. November 30. Rare variantsII.DC

Design – extreme, etc, sample selection
Analyses, Burden/SKAT (assumption of effect size)
Drug targets identified from genetic studies

Required reading:

Do R, Kathiresan S, Abecasis GR. Exome sequencing and complex disease: practical aspects of rare variant association studies. Hum MolGenet. 2012 Oct 15;21(R1):R1-9.

Sham PC, Purcell SM. Statistical power and significance testing in large-scale genetic studies. Nat Rev Genet. 2014;15(5):335-346.

Suggested reading:

Cohen J, Pertsemlidis A, et al. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet. 2005 Feb;37(2):161-5.

Lecture 11. December 5. Advanced topics 1.SL

Mendelian randomization
Gene-environment interactions.
Mediation analysis, pathway-based analysis, cross-phenotype analysis