CDCV

McClellan J & King M-C 2010 Genetic heterogeneity in human disease. Cell 141:210-217.

  • rare mutations of severe effect are responsible for a substantial portion of complex human disease
  • human disease is characterized by marked genetic heterogeneity, far greater than previously appreciated
  • (1) individually rare mutations collectively play a substantial role in causing complex illnesses
  • (2) the same gene may harbor many (hundreds or even thousands) different rare severe mutations in unrelated affected individuals
  • (3) the same mutation may lead to different clinical manifestations (phenotypes) in different individuals
  • (4) mutations in different genes in the same or related pathways may lead to the same disorder
  • causality in this context can almost never be resolved by large-scale association or case-control studies
  • ancient polymorphisms are shared by all human populations and account for approximately 90% of human variation
  • new alleles constantly arise, at an estimated rate of approximately 175 per diploid human genome per generation
  • collectively, these alleles have generated an immense degree of genetic variation
  • thus the paradox
  • most human variation is ancient and shared, but most alleles are recent and rare
  • a major limitation complicating genome-wide association studies is the potential for cryptic population stratification
  • subtle differences in ancestry between cases and controls can produce spurious association solely due to sampling
  • GWAS study designs typically control for population structure in two ways: by taking into account differences among populations in average allele frequencies and by excluding individual subjects with extreme outlier genotypes
  • these approaches are appropriate and necessary but not sufficient
  • odds ratios of the magnitude generally detected by GWAS (<1.5) can frequently be explained by cryptic population stratification, regardless of the p value associated with them
  • the common disease-common variant model has been the primary focus of human genomics over the last decade
  • if common alleles influenced common diseases, many would have been found by now
  • the issue is not how to develop still larger studies, or how to parse the data still further, but rather whether the common disease-common variant hypothesis has now been tested and found not to apply to most complex human diseases