Kourosh R. Ahmadi

A single-nucleotide polymorphism tagging set for human drug metabolism and transport

Interindividual variability in drug response, ranging from no therapeutic benefit to life-threatening adverse reactions, is influenced by variation in genes that control the absorption, distribution, metabolism and excretion of drugs. We genotyped 904 single-nucleotide polymorphisms (SNPs) from 55 such genes in two population samples (European and Japanese) and identified a set of tagging SNPs that represents the common variation in these genes, both known and unknown. Extensive empirical evaluations, including a direct assessment of association with candidate functional SNPs in a new, larger population sample, validated the performance of these tagging SNPs and confirmed their utility for linkage-disequilibrium mapping in pharmacogenetics. The analyses also suggest that rare variation is not amenable to tagging strategies.

Reply to 'Haplotype block structure of the cytochrome P450 CYP2C gene cluster on chromosome 10'

Walton et al. discuss two points regarding the selection of tagging SNPs (tSNPs) for genetic association studies. The first relates to the genomic boundaries within which tSNPs are selected. The computational constraints on multiple-marker methods of selecting tSNPs make it impractical to consider contiguous stretches of sequence beyond a certain size; beyond this, it is necessary to follow some scheme to subdivide the region. Walton et al. note that the division selected for one of our regions, the polygenic CYP2C region, will influence the tSNP efficiency (i.e., minimizing the number of tSNPs needed to achieve a desired level of power against untyped causal variants). Second, Walton et al. note that there may be long-range haplotypes extending across genes in the CYP2C cluster that may form functional units. As general principles, we agree with both these points. In fact, we were among the first to show that combining smaller regions into single large ones, where possible, led to considerable increases in SNP tagging efficiency1. We also think that the occurrence of two or more genes in strong linkage disequilibrium (LD) could make it useful to consider intergene haplotypes as integrated units in association studies.

A functional polymorphism regulating dopamine beta-hydroxylase influences against Parkinson's disease.

A functional −1021C → T polymorphism in the dopamine β‐hydroxylase gene has been demonstrated to regulate plasma DBH activity. We report that individuals with genetically determined low serum DBH activity (genotype T/T) have protection against Parkinsons disease (p = 0.01). In particular, we observed an underrepresentation of the T/T genotype odds ratio = 0.46 (CI = 0.27‐0.8). Rather than identifying a haplotype, or a marker in linkage disequilibrium with the risk variant, this to our knowledge is the first report directly linking PD susceptibility with a proven functional variant. Ann Neurol 2004

The alpha-synuclein gene in multiple system atrophy

Background: The formation of α-synuclein aggregates may be a critical event in the pathogenesis of multiple system atrophy (MSA). However, the role of this gene in the aetiology of MSA is unknown and untested. Method: The linkage disequilibrium (LD) structure of the α-synuclein gene was established and LD patterns were used to identify a set of tagging single nucleotide polymorphisms (SNPs) that represent 95% of the haplotype diversity across the entire gene. The effect of polymorphisms on the pathological expression of MSA in pathologically confirmed cases was also evaluated. Results and conclusion: In 253 Gilman probable or definite MSA patients, 457 possible, probable, and definite MSA cases and 1472 controls, a frequency difference for the individual tagging SNPs or tag-defined haplotypes was not detected. No effect was observed of polymorphisms on the pathological expression of MSA in pathologically confirmed cases.

The gene responsible for PARK6 Parkinson's disease, PINK1, does not influence common forms of parkinsonism.

Mutations in the PINK1 gene (PARK6), a putative serine‐threonine kinase, cause autosomal recessive Parkinsons disease. PINK1 functions as a protein kinase and confers protective effects in the mitochondria, where it is primarily located. We assessed in a population of European ancestry whether common genetic variation in this novel gene influences nonmendelian forms of Parkinsons disease. We defined the linkage disequilibrium structure of PINK1 and used this to identify a set of tagging single nucleotide polymorphisms that we estimate will efficiently represent all of the common DNA variation in the entire gene. Genotyping these tags in a set of 576 Parkinsons disease patients and 514 controls did not demonstrate a case–control partition for allele or for haplotype and thus provides evidence against the existence of a common functional variants in PINK1 that has a strong influence on PD risk. Ann Neurol 2004;56:329–335

NR4A2 genetic variation in sporadic Parkinson's disease: a genewide approach.

The NR4A2 gene, which may cause autosomal dominant Parkinsons disease (PD), has also been reported to be a susceptibility factor for sporadic PD. Here, we use a haplotype‐tagging approach in 802 PD patients and 784 controls and demonstrate that common genetic variation, including NR4A2 haplotypes, does not influence the risk of PD in the Caucasian population.

UCHL-1 gene in multiple system atrophy: A haplotype tagging approach

To date, the etiology of multiple system atrophy (MSA) has proved impenetrable. We investigated the role of genetic variation in the UCHL‐1 gene in MSA and looked for the presence of disease susceptibility alleles. We determined the linkage disequilibrium structure of the gene and employed a haplotype tagging strategy with power to represent 95% of the haplotype diversity. This approach was performed using a set of tagging single nucleotide polymorphisms (SNPs) that can infer the allelic state of all the common SNPs in UCHL‐1 with a high coefficient of determination. This strategy enabled us to scan across the gene and maintain the power to detect signal(s) from any potential functional variant(s). In 257 Gilman‐probable or ‐definite MSA subjects and 1,536 controls, we did not detect a case–control frequency difference for either the tagged haplotypes or for individual tagging SNPs. This search included the S18Y variant of UCHL‐1, which has been reported to be protective in Parkinsons disease.

Population genetic approaches to neurological disease: Parkinson's disease as an example

Parkinsons disease (PD) is a common, progressive, incurable disabling condition. The cause is unknown but over the past few years tremendous progress in our understanding of the genetic bases of this condition has been made. To date, this has almost exclusively come from the study of relatively rare Mendelian forms of the disease and there are no currently, widely accepted common variants known to increase susceptibility. The role that the ‘Mendelian’ genes play in common sporadic forms of PD is unknown. Moreover, most studies in PD can really be described as candidate polymorphism studies rather than true and complete assessments of the genes themselves. We provide a model of how one might tackle some of these issues using Parkinsons disease as an illustration. One of the emerging hypotheses of gene environment interaction in Parkinsons disease is based on drug metabolizing (or xenobiotic) enzymes and their interaction with putative environmental toxins. This motivated us to describe a tagging approach for an extensive but not exhaustive list of 55 drug metabolizing enzyme genes. We use these data to illustrate the power, and some of the limitations of a haplotype tagging approach. We show that haplotype tagging is extremely efficient and works well with only a modest increase in effort through different populations. The tagging approach works much less well if the minor allele frequency is below 5%. However, it will now be possible using these tags to evaluate these genes comprehensively in PD and other neurodegenerative conditions.

Assessment of a DJ-1 (PARK7) polymorphism in Finnish PD

To the Editor:nnWe read with interest the report by Eerola et al.1 that demonstrates lack of association between a DJ-1 promoter polymorphism and Parkinson disease (PD). The authors also claim that their “observations indicate strong linkage disequilibrium (LD) across the gene” and that they provide “compelling evidence that common variation within DJ-1 does not act as a risk factor for PD.” However, their evidence represents an oversimplification of LD architecture and its potential in common trait mapping. …