Mapping copy number variation by population-scale genome sequencing

Mapping copy number variation by population-scale genome sequencing

Ryan E. Mills et al.

Nature 470, 59–65 doi:10.1038/nature09708

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Imputation of sequence variants for identification of genetic risks for Parkinson’s disease. The Lancet, Early Online Publication, 2 February 2011

Imputation of sequence variants for identification of genetic risks for Parkinson’s disease: a meta-analysis of genome-wide association studies:

“The discovery phase consisted of 5333 case and 12 019 control samples, with genotyped and imputed data at 7.689.524 SNPs. The replication phase consisted of 7053 case and 9007 control samples. We identified 11 loci that surpassed the threshold for genome-wide significance. Six were previously identified loci (MAPT, SNCA, HLA-DRB5, BST1, GAK and LRRK2) and five were newly identified loci (ACMSD, STK39, MCCC1/LAMP3, SYT11, and CCDC62/HIP1R). The combined population-attributable risk was 60·3% (95% CI 43·7—69·3). In the risk-profile analysis, the odds ratio in the highest quintile of disease risk was 2·51 (95% CI 2·23—2·83) compared with 1·00 in the lowest quintile of disease risk.”


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Maternal Plasma DNA Sequencing Reveals the Genome-Wide Genetic and Mutational Profile of the Fetus

Maternal Plasma DNA Sequencing Reveals the Genome-Wide Genetic and Mutational Profile of the Fetus

Y. M. D. Lo, K. C. A. Chan, H. Sun, E. Z. Chen, P. Jiang, F. M. F. Lun, Y. W. Zheng, T. Y. Leung, T. K. Lau, C. R. Cantor, R. W. K. Chiu

Sci. Transl. Med. 2, 61ra91 (2010) doi:10.1126/scitranslmed.3001720

Cell-free fetal DNA is present in the plasma of pregnant women. It consists of short DNA fragments among primarily maternally derived DNA fragments. We sequenced a maternal plasma DNA sample at up to 65-fold genomic coverage. We showed that the entire fetal and maternal genomes were represented in maternal plasma at a constant relative proportion. Plasma DNA molecules showed a predictable fragmentation pattern reminiscent of nuclease-cleaved nucleosomes, with the fetal DNA showing a reduction in a 166–base pair (bp) peak relative to a 143-bp peak, when compared with maternal DNA. We constructed a genome-wide genetic map and determined the mutational status of the fetus from the maternal plasma DNA sequences and from information about the paternal genotype and maternal haplotype. Our study suggests the feasibility of using genome-wide scanning to diagnose fetal genetic disorders prenatally in a noninvasive way.

Carrier Testing for Severe Childhood Recessive Diseases by Next-Generation Sequencing

Carrier Testing for Severe Childhood Recessive Diseases by Next-Generation Sequencing

C. J. Bell, D. L. Dinwiddie, N. A. Miller, S. L. Hateley, E. E. Ganusova, J. Mudge, R. J. Langley, L. Zhang, C. C. Lee, F. D. Schilkey, V. Sheth, J. E. Woodward, H. E. Peckham, G. P. Schroth, R. W. Kim, S. F. Kingsmore

Sci. Transl. Med. 3, 65ra4 (2011) doi: 10.1126/scitranslmed.3001756

Of 7028 disorders with suspected Mendelian inheritance, 1139 are recessive and have an established molecular basis. Although individually uncommon, Mendelian diseases collectively account for ~20% of infant mortality and ~10% of pediatric hospitalizations. Preconception screening, together with genetic counseling of carriers, has resulted in remarkable declines in the incidence of several severe recessive diseases including Tay-Sachs disease and cystic fibrosis. However, extension of preconception screening to most severe disease genes has hitherto been impractical. Here, we report a preconception carrier screen for 448 severe recessive childhood diseases. Rather than costly, complete sequencing of the human genome, 7717 regions from 437 target genes were enriched by hybrid capture or microdroplet polymerase chain reaction, sequenced by next-generation sequencing (NGS) to a depth of up to 2.7 gigabases, and assessed with stringent bioinformatic filters. At a resultant 160× average target coverage, 93% of nucleotides had at least 20× coverage, and mutation detection/genotyping had ~95% sensitivity and ~100% specificity for substitution, insertion/deletion, splicing, and gross deletion mutations and single-nucleotide polymorphisms. In 104 unrelated DNA samples, the average genomic carrier burden for severe pediatric recessive mutations was 2.8 and ranged from 0 to 7. The distribution of mutations among sequenced samples appeared random. Twenty-seven percent of mutations cited in the literature were found to be common polymorphisms or misannotated, underscoring the need for better mutation databases as part of a comprehensive carrier testing strategy. Given the magnitude of carrier burden and the lower cost of testing compared to treating these conditions, carrier screening by NGS made available to the general population may be an economical way to reduce the incidence of and ameliorate suffering associated with severe recessive childhood disorders.

Effect of Direct-to-Consumer Genomewide Profiling to Assess Disease Risk

Effect of Direct-to-Consumer Genomewide Profiling to Assess Disease Risk
Cinnamon S. Bloss, Ph.D., Nicholas J. Schork, Ph.D., and Eric J. Topol, M.D.
doi:10.1056/NEJMoa1011893 was published on January 12, 2011, at NEJM

The use of direct-to-consumer genomewide profiling to assess disease risk is controversial, and little is known about the effect of this technology on consumers. We examined the psychological, behavioral, and clinical effects of risk scanning with the Navigenics Health Compass, a commercially available test of uncertain clinical validity and utility.

We recruited subjects from health and technology companies who elected to purchase the Health Compass at a discounted rate. Subjects reported any changes in symptoms of anxiety, intake of dietary fat, and exercise behavior at a mean (±SD) of 5.6±2.4 months after testing, as compared with baseline, along with any testrelated distress and the use of health-screening tests.

From a cohort of 3639 enrolled subjects, 2037 completed follow-up. Primary analyses showed no significant differences between baseline and follow-up in anxiety symptoms (P=0.80), dietary fat intake (P=0.89), or exercise behavior (P=0.61). Secondary analyses revealed that test-related distress was positively correlated with the average estimated lifetime risk among all the assessed conditions (β=0.117, P<0.001). However, 90.3% of subjects who completed follow-up had scores indicating no test-related distress. There was no significant increase in the rate of use of screening tests associated with genomewide profiling, most of which are not considered appropriate for screening asymptomatic persons in any case.

In a selected sample of subjects who completed follow-up after undergoing consumer genomewide testing, such testing did not result in any measurable shortterm changes in psychological health, diet or exercise behavior, or use of screening tests. Potential effects of this type of genetic testing on the population at large are not known. (Funded by the National Institutes of Health and Scripps Health.)

Genetic Link for Depression Furthered by Analysis of 54 Studies

Genetic Link for Depression Furthered by Analysis of 54 Studies:

University of Michigan Health System researchers say that genes determine susceptibility to depression. Their findings challenge a 2009 study that called the genetic link into question and add support to previous research that revealed this link.

“For their research the U-M team examined 54 studies dating from 2001 to 2010 and encompassing nearly 41,000 participants. Details of their analysis are published in the online edition of the Archives of General Psychiatry in a paper titled ‘The Serotonin Transporter Promoter Variant (5-HTTLPR), Stress, and Depression Meta-analysis Revisited.’”

from GEN news highlights: Jan 4, 2011

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