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Genomics & Medicine Personal Genomics The Lancet 2010, 375: 1525-1535. Doug Brutlag Professor Emeritus of Biochemistry & Medicine Stanford University School of Medicine. Low Heritability of Common SNPs.

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Genomics & Medicine

Personal Genomics

The Lancet 2010, 375: 1525-1535.

Doug Brutlag

Professor Emeritus of Biochemistry & Medicine

Stanford University School of Medicine

Low Heritability of Common SNPs

Odds Ratio

  • Rare High Penetrance Variants Carry High Risk

  • Common SNPs Carry Low Risk

  • Multiple Variants May Increase Risk Synergistically

  • Common SNPs Associated with Genes Containing High Risk Alleles

  • Common SNPs Associations can Suggest Regions to Sequence in Cohorts or Trios or Subpopulations

Manolio et al. Nature 461, 747-753 (2009)

Disease Genes are Often Enriched in Subpopulations

  • Subpopulations are often enriched for disease alleles

  • Subpopulations can cause synthetic SNP associations

  • Focusing on a subpopulations will eliminate synthetic SNP associations

  • Focusing on subpopulations eliminates need for population stratification adjustments

  • Egypt is a haplotype heaven!

    • Highest frequency of genetic (SNP) variations

    • High numbers of genetic subpopulations due to multiple migrations and invasions

    • Greeks, Romans, Turks, Persians etc.

Summary ofGenome-Wide Association Studies

  • Genome-wide association studies make no assumptions about disease mechanism or cause

  • Genome-wide association studies usually discover only genetic correlations, not causal mutations

  • Genome-wide associations suggest:

    • Genes and regions one must analyze by re-sequencing for causal alleles

    • Subpopulations that may be enriched for causal or preventive alleles

    • Genes and gene products for functional and structural studies

    • Genes to examine for regulatory studies

  • Genome-wide association studies coupled with proper biological and structural studies can lead to:

    • Unexpected causes for disease

    • Novel mechanisms for disease (missense mutations, regulatory changes, alternative splicing, copy number variation etc.)

    • Multiple genes and multiple pathways involved in disease

    • Novel diagnostics and prognosis

    • Novel treatments

Genetic Loci Associated with Hypertriglyceridemia

Novel Rare Variants in GWAS Genes for Hypertriglyceridemia

Rare Variant Accumulation in Hypertriglyceridemia

So What Can We Learn fromPersonal Genomics?

  • Disease risk for common diseases

    • Genetic predisposition towards a disease (relative risk or odds ratio)

    • Genetic versus environmental contributions to disease (penetrance)

    • How to alter your environment and behavior to avoid the disease

  • Disease Carrier status

    • Premarital genetic counseling

    • Preimplantation genetic diagnosis

    • Neonatal diagnosis

      • Amniocentesis

      • Chorion villus sampling (CVS)

      • Fetal cells in pregnant mothers blood

  • Familial traits, diseases and relationships

    • Known family diseases (breast cancers, colorectal cancer, lysosome storage diseases, etc.)

    • Paternity (10% of people do not know their true biological father)

    • Maternity (about 1% of people do not know their true biological mother)

    • Inbreeding and incest lead to increased homozygosity and recessive diseases

    • Orphans can find family relations

  • Pharmacogenomics and Pharmacogenetics: Drug susceptibility

    • Efficacy of common drugs

    • Adverse reactions to common drugs

  • Ancestry

    • One can follow maternal line using mitochondrial DNA SNPs

    • Males can follow paternal line using Y chromosome SNPs

    • Shared haplotypes with recent relatives (up to 5th cousins)


23andMe Kit

23andMe Spittoon

23andMe Sample Tube

23andMe Tube in Envelope

23andMe Fedex Mailer

Choice of GWAS Studies

  • Common traits of broad interest

    • Prevalence of > 1%

    • Report Mendelian traits when possible

    • Focus on drug responses

  • Avoid false discoveries

    • Large case-control studies > 750 cases

    • Highly significant expectation values (<0.01 errors)

    • Published in reputable journals

    • Studies that have been replicated

  • May impute highly linked missing SNPs

  • Calculate likelihood and odds ratio using customers ethnicity as detected

  • Distinguish preliminary studies (non-replicated or smaller sample sizes) from established research.

23andMe Login

23andMe Disease Risks

23andME Opt-In Statement

23andMe Carrier Status

23andMe Carrier Status forAlpha-1 Antitrypsin Deficiency

23andMe Drug Responses

Clopidogrel (Plavix®) Efficacy

23andMe Traits

23andMe Traits

23andMe Maternal Inheritance

23andMe Paternal Inheritance

23andMe Relative Finder

What is a Fifth Cousin?

23andMe Ancestry Painting

23andMe Global Similarity

23andMe Ancestry Labs

23andWe Discoveries

23andWe Discoveries

INFORMED Medical Decisions

INFORMED for 23andMe Customers










Navigenics Compass Program

Navigenics Conditions Covered

DNAdirect: Clinical Genetic Testing

DNAdirect: Clinical Genetic Testing

Personal Genomics References

  • Clinical Assessment Incorporating a Personal Genome. Ashley, E. et al. (2010)

    Lancet 375, 1525-1535.

  • Emerging genomic applications in coronary artery disease. Damani SB,

    Topal EJ, JACC Cardiovasc. Intervention (2011). 4:473-482.

  • Clinical applicability of sequence variations in genes related to drug

    metabolism. Stojiljkovic M, Patrinos GP, Pavlovic S. (2011) Curr Drug Metab.


  • Clinical pharmacogenetics and potential application in personalized medicine.

    Zhou et al., (2008) Curr Drug Metab. 9(8):738-84.

  • Genes, mutations, and human inherited disease at the dawn of the age of

    personalized genomics. Cooper et al (2010) Hum Mutat. 31(6):631-55.

  • Web-based, participant-driven studies yield novel genetic associations for

    common traits. Eriksson et al. (2010) PLoS Genetics 6, e1000993.

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