Systematic investigation of genetic variability in 111 human genes—implications for studying variable drug response

Freudenberg-Hua, Yun; Freudenberg, Jan; Winantea, Jane; Kluck, Nadine; Cichon, Sven; Brüss, Michael; Propping, Peter; Nöthen, Markus M.

doi:10.1038/sj.tpj.6500306

Cited by 15 publications

(8 citation statements)

References 35 publications

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“…41 More recent studies showed a significantly lower allele frequency for human SNPs from conserved noncoding regions, 3,42 consistent with the ongoing action of purifying selection in the human lineage. In the present study, we again observe an excess of rare variants in genomic regions that are conserved between human and rodents, as compared to nonconserved regions.…”

Section: Discussionmentioning

confidence: 96%

“…This fraction of unreported SNPs is quite large, when compared to the fraction of SNPs discovered in coding regions on independent datasets and taking into account the strong increase in public SNP database size. 3 To assess the significance of this difference in Tajima's D between controls and cases, we randomly permuted the affection status of sequenced individuals. In 2400 out of totally 100 000 random permutations, we found a stronger decrease of Tajima's D in the case sample than in the observed data (P ¼ 0.024, one-sided test for smaller Tajima's D among patients).…”

Section: Overall Analysis Of Nucleotide Diversitymentioning

confidence: 99%

“…Within gene control regions, preference was given to genomic regions that are highly conserved between human and rodents. Studies of human single nucleotide polymorphisms (SNPs) showed that these regions display a signature of purifying selection, 3 what makes them first choice targets in the search for disease mutations. Although some examples for phenotypic effects of sequence variation in conserved noncoding regions exist, 4 according to our knowledge no sequencing study so far has focused on nucleotide diversity of these regions among individuals affected with a complex disease phenotype.…”

Section: Introductionmentioning

confidence: 99%

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A summary statistic approach to sequence variation in noncoding regions of six schizophrenia-associated gene loci

et al. 2006

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In order to explore the role of noncoding variants in the genetics of schizophrenia, we sequenced 27 kb of noncoding DNA from the gene loci RAC-alpha serine/threonine-protein kinase (AKT1), brain-derived neurotrophic factor (BDNF), dopamine receptor-3 (DRD3), dystrobrevin binding protein-1 (DTNBP1), neuregulin-1 (NRG1) and regulator of G-protein signaling-4 (RGS4) in 37 schizophrenia patients and 25 healthy controls. To compare the allele frequency spectrum between the two samples, we separately computed Tajima's D-value for each sample. The results showed a smaller Tajima's D-value in the case sample, pointing to an excess of rare variants as compared to the control sample. When randomly permuting the affection status of sequenced individuals, we observed a stronger decrease of Tajima's D in 2400 out of 100 000 permutations, corresponding to a P-value of 0.024 in a one-sided test. Thus, rare variants are significantly enriched in the schizophrenia sample, indicating the existence of disease-related sequence alterations. When categorizing the sequenced fragments according to their level of humanrodent conservation or according to their gene locus, we observed a wide range of diversity parameter estimates. Rare variants were enriched in conserved regions as compared to nonconserved regions in both samples. Nevertheless, rare variants remained more common among patients, suggesting an increased number of variants under purifying selection in this sample. Finally, we performed a heuristic search for the subset of gene loci, which jointly produces the strongest difference between controls and cases. This showed a more prominent role of variants from the loci AKT1, BDNF and RGS4. Taken together, our approach provides promising strategy to investigate the genetics of schizophrenia and related phenotypes.

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Section: Discussionmentioning

confidence: 96%

Section: Overall Analysis Of Nucleotide Diversitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A summary statistic approach to sequence variation in noncoding regions of six schizophrenia-associated gene loci

et al. 2006

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“…Personalized medicine involves preventative, diagnostic, and therapeutic interventions, with risk defined through genetics as well as clinical and family histories. There are already several well-known examples of personalized medicine based upon using pharmacogenomics [1,2,3,4,5,6,7,8]. However, pharmacogenomic-based diagnostics and therapeutics have not yet been fully incorporated into routine clinical practice.…”

Section: Introductionmentioning

confidence: 99%

Assessing Patient Readiness for the Clinical Adoption of Personalized Medicine

Issa

Tufail

Hutchinson

et al. 2009

Public Health Genomics

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Background/Aims: Although pharmacogenomics-based diagnostics and therapeutics are increasingly being translated into personalized medicine applications, relatively little evidence exists about how novel pharmacogenomics-based technologies will be accepted and adopted by patients. It is important to understand the characteristics of genomic diagnostics and targeted therapeutics that might impact utilization or serve as barriers to adoption of these novel technologies in order to formulate appropriate policies and procedures. The objective of this study was to investigate patients’ understanding and knowledge of personalized medicine and the process of decision-making regarding pharmacogenomics testing and targeted therapeutics and to better understand how patients value receiving pharmacogenomics-based care. Methods: We conducted 4 focus groups with 8–10 individuals in each group with patients recruited from out-patient clinics at The Methodist Hospital in Houston, Tex., USA. Results: The use of genomic diagnostics and targeted therapeutics to facilitate personalized medicine has considerable support from patients. However, our data revealed that participants were concerned with issues surrounding privacy and confidentiality of genetic test results, particularly with respect to access of information by insurers, with potential costs of testing and issues related to accuracy of test results. Questions regarding willingness to pay revealed that patients would be more willing to pay out-of-pocket if the disease associated with pharmacogenomic testing for treatment was perceived to be high risk (e.g., colorectal cancer) versus a chronic condition that was perceived as lower risk (e.g., high cholesterol). Conclusion: As the personalized medicine approach is increasingly incorporated into health care, understanding patients’ needs and their readiness to adopt these novel technologies will become progressively more important for the development of appropriate health policies.

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“…61 Additionally, it has been found that genetic diversity decreases in noncoding regions whereas diversity of coding nonsynonymous SNPs is lower in regions containing a known protein sequence motif in individuals of European origin. 62 Drug treatment may be tailored for greater effect if important genetic variation exists between racial and ethnic groups. By knowing these variants, patients can be classified into low, intermediate and high dose groups.…”

Section: Ethnicitymentioning

confidence: 99%