NEJM_Goldstein09_common_variation - P ERS PE C T IV E...

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PERSPECTIVE n engl j med 360;17 april 23 , 2009 1696 Common Genetic Variation and Human Traits David B. Goldstein, Ph.D. Common Genetic Variation and Human Traits T he human genome has been cracked wide open in recent years and is spilling many of its secrets. More than 100 genome- wide association studies have been conducted for scores of hu- man diseases, identifying hun- dreds of polymorphisms that are widely seen to influence disease risk. After many years in which the study of complex human traits was mired in false claims and methodologic inconsistencies, ge- nomics has brought not only com- prehensive representation of com- mon variation but also welcome rigor in the interpretation of sta- tistical evidence. Researchers now know how to properly account for most of the multiple hypothesis testing involved in mining the ge- nome for associations, and most reported associations reflect real biologic causation. But do they matter? Unfortunately, most common gene variants that are implicated by such studies are responsible for only a small fraction of the genetic variation that we know exists. This observation is par- ticularly troubling because the studies are largely comprehensive in terms of common single-nucle- otide polymorphisms (SNPs), the genomic markers that are geno- typed and with which disease as- sociations are tested. We’re find- ing the biggest effects that exist for this class of genetic variant, and common variation is packing much less of a phenotypic punch than expected. Some experts em- phasize that small effect sizes don’t necessarily mean that a gene variant is of no interest or use. Effect size is a function of what a variant does: it may change only slightly a gene’s expression or a protein’s function. The gene’s pathway, however, may be deci- sive for a particular condition, or pharmacologic action on the same protein may produce much larger effects in controlling disease. These arguments are reasonable, as far as they go, and there are supporting examples, such as a polymorphism of modest effect in PPARG, a gene that encodes a drug target for diabetes. But the arguments hold only if common genetic variation im- plicates a manageable number of genes. If effect sizes were so small as to require a large chunk of the genome to explain the genet- ic component of a disorder, then no guidance would be provided: in pointing at everything, genet- ics would point at nothing. To assess whether effect sizes are too small in this sense, consider two examples of complex human traits — type 2 diabetes and height. In their recent review, Manolio et al. 1 described seven gene variants that influence the risk of type 2 diabetes. In addition to these variants, the one with the strongest effect on familial aggre- gation is in the TCF7L2 gene. One way to assess a variant’s
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This note was uploaded on 04/21/2010 for the course BIO 89329 taught by Professor Hollingsworth during the Spring '10 term at SUNY Stony Brook.

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NEJM_Goldstein09_common_variation - P ERS PE C T IV E...

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