DNA Pooling Identifies QTLs on Chromosome 4 for General Cognitive Ability in Children

Fisher, P. J.; Turic, Dragana; Williams, Nigel; McGuffin, Peter; Asherson, Philip; Ball, David; Craig, Ian W.; Eley, Thalia C.; Hill, Linzy; Chorney, Karen; Chorney, Michael J.; Benbow, Camilla Persson; Lubinski, David; Plomin, Robert

doi:10.1093/hmg/8.5.915

Cited by 87 publications

(41 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…12,13 Pooled DNA samples have been analysed for several generations of DNA-based genetic markers such as microsatellite and candidate SNPs using several technologies, including using the Affymetrix GeneChip Mapping 100K Array. [14][15][16][17][18][19][20] To date, however, the empirical validity of DNA pooling and genotyping using array technology has not been sufficiently demonstrated to enable researchers to apply the method with confidence in WGA experiments.…”

Section: Introductionmentioning

confidence: 99%

Genomic DNA pooling for whole-genome association scans in complex disease: empirical demonstration of efficacy in rheumatoid arthritis

et al. 2006

View full text Add to dashboard Cite

A pragmatic approach that balances the benefit of a whole-genome association (WGA) experiment against the cost of individual genotyping is to use pooled genomic DNA samples. We aimed to determine the feasibility of this approach in a WGA scan in rheumatoid arthritis (RA) using the validated human leucocyte antigen (HLA) and PTPN22 associations as test loci. A total of 203 269 single-nucleotide polymorphisms (SNPs) on the Affymetrix 100K GeneChip and Illumina Infinium microarrays were examined. A new approach to the estimation of allele frequencies from Affymetrix hybridization intensities was developed involving weighting for quality signals from the probe quartets. SNPs were ranked by z-scores, combined from United Kingdom and New Zealand case-control cohorts. Within a 1.7 Mb HLA region, 33 of the 257 SNPs and at PTPN22, 21 of the 45 SNPs, were ranked within the top 100 associated SNPs genome wide. Within PTPN22, individual genotyping of SNP rs1343125 within MAGI3 confirmed association and provided some evidence for association independent of the PTPN22 620W variant (P ¼ 0.03). Our results emphasize the feasibility of using genomic DNA pooling for the detection of association with complex disease susceptibility alleles. The results also underscore the importance of the HLA and PTPN22 loci in RA aetiology.

show abstract

Section: Introductionmentioning

confidence: 99%

Genomic DNA pooling for whole-genome association scans in complex disease: empirical demonstration of efficacy in rheumatoid arthritis

et al. 2006

View full text Add to dashboard Cite

show abstract

“…Pools need to be constructed as accurately as possible to minimise technical errors. When these precautions are combined with a multi-stage design [11], it is likely that selective DNA pooling will be much more successful in identifying markers worth pursuing by individual genotyping for interval mapping using a halfsibling experimental design.…”

Section: Discussionmentioning

confidence: 99%

Empirical evaluation of selective DNA pooling to map QTL in dairy cattle using a half-sib design by comparison to individual genotyping and interval mapping

Mariasegaram

Robinson²,

Goddard

2007

Genet Sel Evol

View full text Add to dashboard Cite

-This study represents the first attempt at an empirical evaluation of the DNA pooling methodology by comparing it to individual genotyping and interval mapping to detect QTL in a dairy half-sib design. The findings indicated that the use of peak heights from the pool electropherograms without correction for stutter (shadow) product and preferential amplification performed as well as corrected estimates of frequencies. However, errors were found to decrease the power of the experiment at every stage of the pooling and analysis. The main sources of errors include technical errors from DNA quantification, pool construction, inconsistent differential amplification, and from the prevalence of sire alleles in the dams. Additionally, interval mapping using individual genotyping gains information from phenotypic differences between individuals in the same pool and from neighbouring markers, which is lost in a DNA pooling design. These errors cause some differences between the markers detected as significant by pooling and those found significant by interval mapping based on individual selective genotyping. Therefore, it is recommended that pooled genotyping only be used as part of an initial screen with significant results to be confirmed by individual genotyping. Strategies for improving the efficiency of the DNA pooling design are also presented.selective DNA pooling / dairy half-sib design / genome scan / individual selective genotyping

show abstract

“…Pooling has been used successfully with microsatellites in model experiments [37][38][39][40] and to detect evidence of putative QTL for cognitive ability. 41 Pooled genotyping is even more readily applicable to SNPs where problems relating to stutter and differential amplification are irrelevant. Thus we have developed a pooling method based on single-nucleotide extension and DHPLC which should allow large samples to be screened rapidly and cheaply.…”

Section: Genome-wide Association Studiesmentioning

confidence: 99%

Psychiatric genetics: back to the future

Owen

Cardno

2000

Mol Psychiatry

View full text Add to dashboard Cite

For the last decade or more geneticists have been predicting that advances in molecular genetics are going to revolutionise our understanding of psychiatric disorders and human behavior. However, with a few exceptions, these expectations have yet to be fulfilled. As the century draws to a close and we contemplate the prospect of the complete sequence of the human genome it seems timely to consider the state of the field and to consider carefully how it might advance, the problems to be faced and the resources required. Molecular Psychiatry (2000) 5, 22-31.Keywords: molecular; epidemiology; linkage; linkage disequilibrium; phenotype; genomics Much of the optimism surrounding the application of molecular genetics to human disease has resulted from successes in applying these techniques to monogenic disorders. However, common illnesses pose much greater challenges for geneticists because, in the majority of cases, they result from the combined action of a number of different genes (each of which may result in only a modest increase or decrease in liability) as well as environmental influences; a witches' brew termed polygenic, multifactorial causation. Further complexities include the possibility of non-additive genetic effects, including gene-gene interactions (epistasis), and also potential gene-environment interactions. In psychiatry, genetic complexity is compounded by the nosological complexity of the phenotypes, which are best viewed as syndromes rather than diseases. It is rarely possible to validate psychiatric diagnoses on the basis of physical examination or laboratory tests or even to confirm them postmortem, and for many disorders we have little idea of pathogenic mechanisms. Current state of progress Genetic epidemiologyIn spite of these difficulties, genetic epidemiological studies based upon operational research diagnoses have shown that genes play a role in many of the syndromes defined by psychiatric nosology (Table 1) Heritability is the proportion of liability to a disorder accounted for by genetic effects. The heritability estimates are based on twin studies which employed DSM-III-R research diagnoses. NB: the heritabilities should be regarded only as approximations.both genes and environment contribute to most specific diagnostic categories, genetic epidemiologists have begun to explore the extent to which there is overlap in genetic and environmental risk factors between disorders; whether genes influence clinical heterogeneity within disorders and the relationship between genetic susceptibility to disorders and putative environmental risk factors. Patterns of familial co-aggregation have been important in helping us to extend diagnostic boundaries. Examples include the schizophrenic and autistic 'spectrum' disorders that are mild, often sub-clinical phenotypes associated with genetic liability to schizophrenia and autism respectively. 2 There is also evidence of a considerable overlap between the genetic contributions to depression and anxiety. 3 Such findings have important implications for...

show abstract

DNA Pooling Identifies QTLs on Chromosome 4 for General Cognitive Ability in Children

Cited by 87 publications

References 17 publications

Genomic DNA pooling for whole-genome association scans in complex disease: empirical demonstration of efficacy in rheumatoid arthritis

Genomic DNA pooling for whole-genome association scans in complex disease: empirical demonstration of efficacy in rheumatoid arthritis

Empirical evaluation of selective DNA pooling to map QTL in dairy cattle using a half-sib design by comparison to individual genotyping and interval mapping

Psychiatric genetics: back to the future

Contact Info

Product

Resources

About