Exome sequencing in pooled DNA samples to identify maternal pre-eclampsia risk variants

Kaartokallio, Tea; Wang, Jingwen; Heinonen, Seppo; Kajantie, Eero; Kivinen, Katja; Pouta, Anneli; Gerdhem, Paul; Jiao, Hong; Kere, Juha; Laivuori, Hannele

doi:10.1038/srep29085

Cited by 20 publications

(12 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…More than 50 candidate genes for preeclampsia within various pathophysiological paths have been suggested, but no universally accepted susceptibility genes for preeclampsia have yet been identified [ 14 ]. Since preeclampsia probably has a polygenetic aetiology of rare genetic variants, a high-resolution systematic investigation of the whole exome is needed [ 24 , 25 ]. Kaartokallio et al used pooled blood samples for an exome sequencing study, thus comparing the pooled frequency of gene variants to reference data.…”

Section: Introductionmentioning

confidence: 99%

The genetic component of preeclampsia: A whole-exome sequencing study

et al. 2018

View full text Add to dashboard Cite

Preeclampsia is a major cause of maternal and perinatal deaths. The aetiology of preeclampsia is largely unknown but a polygenetic component is assumed. To explore this hypothesis, we performed an in-depth whole-exome sequencing study in women with (cases, N = 50) and without (controls, N = 50) preeclampsia. The women were identified in an unselected cohort of 2,545 pregnant women based on data from the Danish National Patient Registry and the Medical Birth Registry. Matching DNA was obtained from a biobank containing excess blood from routine antenatal care visits. Novogene performed the whole-exome sequencing blinded to preeclampsia status. Variants for comparison between cases and controls were filtered in the Ingenuity Variant Analysis software. We applied two different strategies; a disease association panel approach, which included variants in single genes associated with established clinical risk factors for preeclampsia, and a gene panel approach, which included biological pathways harbouring genes previously reported to be associated with preeclampsia. Variant variability was compared in cases and controls at the level of biological processes, signalling pathways, and in single genes. Regardless of the applied strategy and the level of variability examined, we consistently found positive correlations between variant numbers in cases and controls (all R2s>0.88). Contrary to what was expected, cases carried fewer variants in biological processes and signalling pathways than controls (all p-values ≤0.02). In conclusion, our findings challenge the hypothesis of a polygenetic aetiology for preeclampsia with a common network of susceptibility genes. The greater genetic diversity among controls may suggest a protective role of genetic diversity against the development of preeclampsia.

show abstract

Section: Introductionmentioning

confidence: 99%

The genetic component of preeclampsia: A whole-exome sequencing study

et al. 2018

View full text Add to dashboard Cite

show abstract

“…The poor performance of the technical validation of the exome sequencing results may be due to the DNA pooling design. This strategy saves costs and has been used successfully in other studies 14,15 , which however also reported that it has several limitations (e.g. unequal contributions of different individuals to the DNA pool and variations in sequencing depth in different genes) that can affect the allele frequency estimates.…”

Section: Discussionmentioning

confidence: 99%

“…The strategy of starting with DNA pools, rather than individual samples, was chosen because of the high costs of individual exome sequencing. This approach has already been used successfully to identify genetic variations associated with other clinical conditions and has been found to be cost effective 14,15 .…”

Section: Methodsmentioning

confidence: 99%

Identification of genetic polymorphisms modulating nausea and vomiting in two series of opioid-treated cancer patients

Colombo

Pintarelli

Galvan

et al. 2020

Sci Rep

View full text Add to dashboard Cite

Nausea and vomiting are often associated with opioid analgesia in cancer patients; however, only a subset of patients develop such side effects. Here, we tested the hypothesis that the occurrence of nausea and vomiting is modulated by the genetic background of the patients. Whole exome sequencing of DNA pools from patients with either low (n = 937) or high (n = 557) nausea and vomiting intensity, recruited in the European Pharmacogenetic Opioid Study, revealed a preliminary association of 53 polymorphisms. PCR-based genotyping of 45 of these polymorphisms in the individual patients of the same series confirmed the association for six SNPs in AIM1L, CLCC1, MUC16, PDE3A, POM121L2, and ZNF165 genes. Genotyping of the same 45 polymorphisms in 264 patients of the Italian CERP study, also treated with opioids for cancer pain, instead confirmed the association for two SNPs in ZNF568 and PDE3A genes. Only one SNP, rs12305038 in PDE3A, was confirmed in both series, although with opposite effects of the minor allele on the investigated phenotype. Overall, our findings suggest that genetic factors are indeed associated with nausea and vomiting in opioid-treated cancer patients, but the role of individual polymorphisms may be weak. Opioid treatment is a standard and consolidated therapy for relieving pain in advanced cancer patients 1. However, a variable percentage of patients experience poor treatment benefit and also develop side effects 2,3. Nausea and vomiting occur frequently in opioid therapy for cancer-related pain. A recent systematic review of 25 prospective studies 4 found that approximately 50% of patients who took morphine, oxycodone, fentanyl, methadone, or hydromorphone for cancer-related pain experienced nausea (ranging from 3% to 85%), whereas the occurrence of vomiting in the same patients ranged from 4% to 50% in the various studies. The wide range in occurrence of nausea and vomiting suggests that genetic factors are involved in individual susceptibility to these side effects. So far, only a few studies have reported genetic polymorphisms associated with the variability in nausea and vomiting among cancer patients receiving opioids. One multicenter European study that examined polymorphisms in genes related to opioid and nausea/vomiting signaling pathways, in 1579 patients receiving opioids for cancer pain, found associations between these side effects and polymorphisms in HTR3B, COMT, and CHRM3 genes 5. Another study looked specifically at polymorphisms in CYP2D6, a gene that encodes an opioid-metabolizing enzyme, and found no effect of CYP2D6 genotypes on nausea 6. Both of these studies followed a candidate-gene approach, involving the analysis of known polymorphisms in genes already shown to participate in opioid action or metabolism or in the expression of nausea and vomiting. A candidate-gene approach, which permits the analysis of only a few genes, has major limitations in the study of the genetics of complex

show abstract

“…Library preparation and whole exome sequencing on the pre-eclampsia study have been previously described 22 . The same setting was applied to the scoliosis study as well 17 .…”

Section: Methodsmentioning

confidence: 99%

“…The SNV validation by genotyping has been previously described in the scoliosis study 17 and the pre-eclampsia study 22 . In brief, the variants selected for validation were genotyped using Sequenom MassARRAY system (San Diego, California, United States) on the samples included in the WES.…”

Section: Methodsmentioning

confidence: 99%

Investigation of rare and low-frequency variants using high-throughput sequencing with pooled DNA samples

Wang

Skoog

Einarsdottir

et al. 2016

Sci Rep

Self Cite

View full text Add to dashboard Cite

High-throughput sequencing using pooled DNA samples can facilitate genome-wide studies on rare and low-frequency variants in a large population. Some major questions concerning the pooling sequencing strategy are whether rare and low-frequency variants can be detected reliably, and whether estimated minor allele frequencies (MAFs) can represent the actual values obtained from individually genotyped samples. In this study, we evaluated MAF estimates using three variant detection tools with two sets of pooled whole exome sequencing (WES) and one set of pooled whole genome sequencing (WGS) data. Both GATK and Freebayes displayed high sensitivity, specificity and accuracy when detecting rare or low-frequency variants. For the WGS study, 56% of the low-frequency variants in Illumina array have identical MAFs and 26% have one allele difference between sequencing and individual genotyping data. The MAF estimates from WGS correlated well (r = 0.94) with those from Illumina arrays. The MAFs from the pooled WES data also showed high concordance (r = 0.88) with those from the individual genotyping data. In conclusion, the MAFs estimated from pooled DNA sequencing data reflect the MAFs in individually genotyped samples well. The pooling strategy can thus be a rapid and cost-effective approach for the initial screening in large-scale association studies.

show abstract

Exome sequencing in pooled DNA samples to identify maternal pre-eclampsia risk variants

Cited by 20 publications

References 51 publications

The genetic component of preeclampsia: A whole-exome sequencing study

The genetic component of preeclampsia: A whole-exome sequencing study

Identification of genetic polymorphisms modulating nausea and vomiting in two series of opioid-treated cancer patients

Investigation of rare and low-frequency variants using high-throughput sequencing with pooled DNA samples

Contact Info

Product

Resources

About