![Sample our Bioscience journals, sign in here to start your access, Latest two full volumes FREE to you for 14 days]({"type":"image" , "src" : "/sda/5925/TOC-Subject-Sample-2021-Bioscience.jpg"})
Abstract
This review is dedicated to the memory of our dear friend and colleague Professor Werner Kalow (1916–2008)
A brief history of human genetics and genomics is provided, comparing recent progress in those fields with that in pharmacogenetics and pharmacogenomics, which are subsets of genetics and genomics, respectively. Sequencing of the entire human genome, the mapping of common haplotypes of single-nucleotide polymorphisms (SNPs), and cost-effective genotyping technologies leading to genome-wide association (GWA) studies—have combined convincingly in the past several years to demonstrate the requirements needed to separate true associations from the plethora of false positives. While research in human genetics has moved from monogenic to oligogenic to complex diseases, its pharmacogenetics branch has followed, usually a few years behind. The continuous discoveries, even today, of new surprises about our genome cause us to question reviews declaring that “personalized medicine is almost here” or that “individualized drug therapy will soon be a reality.” As summarized herein, numerous reasons exist to show that an “unequivocal genotype” or even an “unequivocal phenotype” is virtually impossible to achieve in current limited-size studies of human populations. This problem (of insufficiently stringent criteria) leads to a decrease in statistical power and, consequently, equivocal interpretation of most genotype-phenotype association studies. It remains unclear whether personalized medicine or individualized drug therapy will ever be achievable by means of DNA testing alone.
| ABBREVIATIONS | ||
| CEPH: | = | Centre d'Etude du Polymorphisme Humain |
| CEU: | = | Individuals from Utah, having Caucasian ancestry from northern and western Europe |
| CHB: | = | Han Chinese in Beijing, China |
| CI: | = | Confidence interval |
| CNVs: | = | Copy-number variations |
| DNaseI: | = | E ndonuclease that digests double- or single-stranded DNA into oligonucleotides or mononucleotides |
| EDP: | = | Extreme discordant phenotype |
| EGP: | = | Environmental Genome Project |
| EM: | = | Extensive-metabolizer |
| ENCODE: | = | Encyclopedia of DNA Elements |
| G6PD: | = | Glucose-6-phosphate dehydrogenase |
| GRR: | = | Genotypic relative risk |
| GWA: | = | Genome-wide association |
| HGP: | = | Human Genome Project |
| hPpM: | = | High-penetrance predominantly monogenic |
| HD: | = | Huntington disease |
| JPT: | = | Japanese in Tokyo, Japan |
| LD: | = | Linkage disequilibrium |
| LOD: | = | Logarithm of the odds ratio for linkage |
| MAF: | = | Minor allele frequency |
| OR: | = | Odds ratio |
| PKU: | = | Phenylketonuria |
| PM: | = | Poor-metabolizer |
| QTLs: | = | Quantitative trait loci |
| SNPs: | = | Single-nucleotide polymorphisms |
| UM: | = | Ultrarapid metabolizer |
| XMEs: | = | Xenobiotic-metabolizing enzymes |
| XRTs: | = | XME-related transporters |
| YRI: | = | Yoruba in Ibadan, Nigeria |
ACKNOWLEDGMENTS
We thank our many colleagues for a careful reading of this manuscript. This work was supported, in part, by NIH P30 ES06096 (D.W.N.).