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Will Investments in Biobanks, Prospective Cohorts, and Markers Of The Pharmacogenomics Journal (2005) 5, 75–80 & 2005 Nature Publishing Group All rights reserved 1470-269X/05 $30.00 www.nature.com/tpj EELS (Ethical, Economic, Legal & Social) ARTICLE different single-nucleotide poly- Will investments in biobanks, morphisms for some bases within that segment). As such, nearby alleles in prospective cohorts, and markers the same haplotype are inherited to- gether more often than is expected by of common patterns of variation chance, a phenomenon that is called ‘linkage disequilibrium’. Owing to that benefit other populations for drug coinheritance, haplotypes offer a way of summarizing the genetic variation response and disease susceptibility found within them. Researchers need identify only a few SNPs (called ‘tag SNPs’) to identify the longer haplo- gene discovery? type, which greatly decreases genotyp- ing costs for gene discovery.6 1 2 MW Foster and RR Sharp Those tag SNPs can be used to look for patterns or similarities in inter- 1Department of Anthropology, University of Oklahoma, Norman, OK, USA; individual genetic variation among 2Center for Medical Ethics and Health Policy, Baylor College of Medicine, those affected by a disease or drug Houston, TX, USA response when compared with un- affected controls (ie an association study). The rationale for this strategy is that those similarities (most of The Pharmacogenomics Journal (2005) 5, BACKGROUND which will not contribute to the drug 75–80. doi:10.1038/sj.tpj.6500295 The International HapMap Project, at response or disease in question) will Published online 25 January 2005 US $120 million perhaps the most allow researchers to narrow the possi- high-profile example of infrastructure ble chromosomal regions in which a investment in the next generation of contributing gene may be located.7,8 genetic research, is intended to pro- High-throughput technologies, de- Tag SNPs can be tested for their vide a set of markers to facilitate cost- creasing costs for genotyping, association with a drug response or effective association studies. To that and genomic resources that promise an increased susceptibility to a disease, end, the HapMap is using samples to reduce the number of genotypes with the idea that the actual contri- from four populations (Yoruba in required to scan the genome (such as buting gene(s) will be located nearby Ibadan, Nigeria; Japanese in Tokyo, the International HapMap Project) the associated marker(s). Other tech- Japan; Han Chinese in Beijing, China; soon will make association studies a niques, such as positional cloning, more successful strategy for identify- and Utah residents with ancestry from then can be used to identify the gene ing genetic contributors to disease Northern and Western Europe known or genes in question. susceptibility and drug response.1,2 as the CEPH samples) to construct a To have sufficient power to detect Accordingly, both nonprofit funders genomic resource that will identify the weak-to-intermediate genetic effects, and biotechnology companies cur- common (45%) haplotypes that are association studies will require very rently are investing in infrastructure estimated as structuring 80–85% of all large numbers of DNA samples linked 3,4 for association studies. Elements of genetic variation among humans. with phenotypic information. In addi- that emerging infrastructure such as Preliminary research suggests that the tion to traditional case–control or prospective cohorts and biobanks are same three to five common haplotypes cross-sectional samples, those data being developed with participants will be found at any given chromo- increasingly will come either from from a limited number of populations somal region in most if not all human prospective cohorts or from biobanks with the goal of applying their populations, although in different (which often include both retrospec- findings to many other populations. frequencies.5 tive and prospective data), the estab- However, not all phenotypes and A haplotype is a linear sequence of lishment and maintenance of which populations may be as suitable for bases on the same chromosome (usual- also will require significant funding this approach as others. Which ly varying in length from 100 to and effort. The advantage of biobanks populations and phenotypes will 100 000 bases) that is identifiable as and prospective cohorts over case– benefit and which will not in the one of a number of alternative struc- control designs is that the former coming era of large-scale association tures for a given segment of that provide longitudinal data for multiple studies? chromosome (by virtue of there being phenotypes. Investments in large-scale genomics project MW Foster and RR Sharp 76 The questions about the overall Project diverged from one another), and recombination events have added association study strategy, though, requiring that different tag SNPs be to those original variants, although are, first, the extent to which ‘com- developed for each population or the greater allelic diversity continues mon’ markers or patterns of variation sample studied.16,17 to be found in ancestral African popu- discovered in a few (albeit carefully These critiques will be neither gen- lations. Founder effects among those chosen) populations will be useful for erally proven nor disproved. Rather, who migrated out of Africa decreased gene discovery in other populations they will apply to some populations, the allelic diversity in non-African and, second, the applicability of gene some phenotypes, and some genomic populations, while subsequent popu- discoveries in a given population to regions but not to all. Such factors as lation bottlenecks also tended to re- other populations. Positive answers to the effect size of a disease susceptibi- duce diversity. Nevertheless, genetic both these questions often have been lity or drug response locus, the fre- drift can increase the frequency of linked because it makes no sense to quency of the disease or drug response otherwise rare genetic patterns and construct a HapMap without large allele(s), the frequency of the marker variants, particularly when those al- biobanks and prospective cohorts in allele(s), and the extent of linkage ready exist in the population. which to use tag SNPs. At the same disequilibrium between the marker In contrast, locally varying selection time, large biobanks and cohorts are and the disease susceptibility or drug pressures have been more responsible best utilized for association studies, response locus will figure into a for- for differences in frequencies of allelic the cost of which can become prohi- mula that can indicate the likelihood variants, with selection against a trait bitive without markers like tag SNPs of success for an association study for a tending to increase rare alleles and that can reduce the number of bases specific phenotype in a particular positive selection increasing the fre- that must be genotyped. population with a given study de- quency of adaptive alleles, while simi- The debate that has developed sign.15 We can, though, consider po- lar environmental conditions across around these two questions has fo- tential scenarios in which tag SNPs populations have tended to promote cused on the applicability of what has and disease susceptibility and drug– selection of alleles in similar frequen- been called the Common Disease/ response variants discovered using cies. Selection sometimes also can Common Variant (or CD/CV) hypo- prospective cohorts and biobanks affect the frequency of patterns of thesis,9 which supports the view that in some populations may be useful variation, such as when an ancestral one or a few genetic contributors in other populations. These scena- haplotype is nearby an allele on which account for significant numbers of rios more fully describe the range of there is a positive or negative selective cases of many common, complex dis- logical possibilities of which the CD/ pressure. eases in most or all populations10,11 CV hypothesis is but one. It is useful Indeed, the continued sorting and The CD/CV hypothesis, though, is not to consider that fuller range to think resorting of individuals over time into unique to disease expression and can more systematically about the ways in loosely bounded, transitory groupings be extended to other phenotypes such which investments in the infrastruc- (ie populations) each of which has as drug response. ture to support association studies experienced somewhat unique, dyna- Several critiques, however, have (and investigators’ and funders’ future mically varying selection and demo- been made of the CD/CV strategy choices increasingly to rely on those graphic events has resulted in the underlying the infrastructure being studies) may result in disparities in the different scenarios for contemporary developed around association studies. benefits of genetic research. populations described below. First, some have argued that common variants may be the exception rather Common Phenotype, Common than the rule, and that most common SCENARIOS pattern, Common Variant (CCC) diseases and drug responses may have Scenarios in which genetic discoveries This is what usually is meant by the multiple, rare (o1% frequency) genet- in one population may benefit other CD/CV hypothesis. SNPs, haplotypes, ic contributors that likely vary con- populations are best understood and variant alleles that are common siderably by population.12–14 Second, against the framework of human po- across contemporary populations most the effects of some common variants
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