In the April 16, 2010, issue of Cell Jon McClellan and Mary-Claire King published a commentary that addressed the nature of the genetic variation that accounts for common human diseases, an issue of profound importance in evolutionary medicine.  The authors also address some methodological aspects of current research in this domain.  Their forceful critique of genome-wide association studies (GWAS) has elicited two spirited responses from investigators who have been active in GWAS (Klein et al., 2010, Wang et al., 2010).

McClellan and King argue that human diseases generally arise from diverse genetic sources such that pathologic processes occurring in different individuals but classified under the same diagnostic label may be caused by different alleles at the same locus or alleles at different loci (i.e., different loci in different individuals).  Thus, a single locus may harbor many dozens or hundreds of distinct mutations that predispose to the clinical condition under consideration.  Furthermore, this variation in causal genetic elements may be reflected in considerable phenotypic variation that nevertheless still occurs within a sufficiently limited range to plausibly fit within a single diagnostic category. 

McClellan and King note an additional wrinkle in that the same mutation at a locus may be associated with different pathologies in different genetic contexts, i.e. the same mutation can be associated with different diseases in different bodies.  They cite a study (Chubb et al., 2008) of a Scottish family in which the same chromosomal translocation was associated with schizophrenia, bipolar disease, major depressive disorder or no mental illness.  A similar phenomenon has been seen with mitochondrial mutations (e.g., the point mutation m.3243A>G) that lead to distinct syndromes (Chinnery, 2008, 2010).

A further key contention of McClellan and King is that the genomics community had largely assumed that common diseases were caused by common genetic variants.  However, McClellan and King claim that the preponderance of evidence now supports the view that such diseases are more often due to many different individually rare mutations.  Relevant evidence pertaining to the genetic causes of breast and other cancers, nonsyndromic hearing loss, disorders of lipid matebolism, and neuropsychiatric disorders such as autism and schizophrenia is presented in some detail to support their assertion.  The responses by Klein et al. and Wang et al. cite evidence to support the view that some common variants are pathogenetically involved in common diseases.  Of course, these two types of genetic causation are not mutually exclusive when considering populations of individuals affected by a given medical condition.  In fact, it is plausible that rare and common genetic variants could simultaneously contribute to a disease in a single individual.

McClellan and King and their critics all seem to expect great new insights from whole-genome sequencing studies that are just getting underway.  I expect that the relative contributions of common versus rare genetic variants to human disease will be substantially clarified over the next five to ten years.  Even so, McClellan and King acknowledge that the extent of human genetic heterogeneity, variable penetrance, epistasis, epigenetic mechanisms, and gene-environment interactions are likely to represent significant challenges to investigators hoping to identify disease-causing genetic variants by using high-throughput sequencing of partial or full human genomes.  As noted by McClellan and King, there may be many thousands of rare genetic variants in a typical individual (McKernan, 2009), although a substantially greater number of human genomes may need to be analyzed in depth before it is possible to comment with confidence on both the average number of such variants and the range of values.

The tendency for mutations associated with a given disease or condition to occur in genes encoding gene products jointly involved in common pathways is another important point emphasized in the article by McClellan and King.  The critics of the commentary also seem to accept the importance of this pattern of disease-related genetic variation. 

Finally, a point that neither McClellan and King nor their critics directly address is that pathogenetic pathways do not consist solely of gene products encoded at loci that vary between affected and unaffected individuals.  In other words, gene products in affected individuals that are identical to those in unaffected individuals can also contribute in major ways to the relevant pathophysiological processes.  Furthermore, drugs targeted to such gene products may sometimes be clinically useful, like drugs targeted to the gene products encoded by disease-associated gene variants.


McClellan J, King MC. Genetic heterogeneity in human disease. Cell. 2010 Apr 6;141(2):210-7. PubMed PMID: 20403315.

Klein RJ, Xu X, Mukherjee S, Willis J, Hayes J. Successes of genome-wide association studies. Cell. 2010 Aug 6;142(3):350-1; author reply 353-5. PubMed PMID: 20691890.

Wang K, Bucan M, Grant SF, Schellenberg G, Hakonarson H. Strategies for genetic studies of complex diseases. Cell. 2010 Aug 6;142(3):351-3; author reply 353-5. PubMed PMID: 20691891.

Chubb JE, Bradshaw NJ, Soares DC, Porteous DJ, Millar JK. The DISC locus in psychiatric illness. Mol Psychiatry. 2008 Jan;13(1):36-64. Epub 2007 Oct 2. Review. PubMed PMID: 17912248.

Chinnery, PF. Mitochondrial disorders overview. Gene Reviews. 2008, 2010. PMID: 20301403.

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