Genome sequencing elucidates Sardinian genetic architecture and augments association analyses for lipid and blood inflammatory markers

Sidore, Carlo; Busonero, Fabio; Maschio, Andrea; Porcu, Eleonora; Naitza, Silvia; Żołędziewska, Magdalena; Mulas, Antonella; Pistis, Giorgio; Steri, Maristella; Danjou, Fabrice; Kwong, Alan; Vecchyo, Vicente Diego Ortega Del; Chiang, Charleston W.K.; Bragg‐Gresham, Jennifer L.; Pitzalis, Maristella; Nagaraja, Ramaiah; Tarrier, Brendan; Brennan, Christine; Uzzau, Sergio; Fuchsberger, Christian; Atzeni, Rossano; Reinier, Frédéric; Berutti, Riccardo; Huang, Jie; Timpson, Nicholas J.; Toniolo, Daniela; Gasparini, Paolo; Malerba, Giovanni; Dedoussis, George; Zeggini, Eleftheria; Soranzo, Nicole; Jones, Chris; Lyons, Robert H.; Angius, Andrea; Kang, Hyun Min; Novembre, John; Sanna, Serena; Schlessinger, David; Cucca, Francesco; Abecasis, Gonçalo R.

doi:10.1038/ng.3368

Cited by 224 publications

(245 citation statements)

References 77 publications

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“…However, this result does not undermine the importance to carry out population-specific WGS projects, since 51 % of the variants identified in French Canadians are not currently available in public databases (and would not have been imputed using HRC alone). This is consistent with the discovery by low-pass WGS of population-specific variants of large effect size on human complex phenotypes (Danjou et al 2015;Sidore et al 2015;Zoledziewska et al 2015). WGS data also provide the opportunity to explore other type of DNA sequence polymorphisms, such as structural and highly repetitive variants.…”

Section: Discussionsupporting

confidence: 78%

“…The 1000 Genomes Project implemented successfully this approach in individuals from several populations from across the globe (1000Genomes Project Consortium 20101000Genomes Project Consortium 2012. The SardiNIA and Genome of the Netherlands consortia also used lowto-intermediate coverage WGS to find common and rare population-specific variants (Danjou et al 2015; Genome of the Netherlands 2014; Sidore et al 2015;Zoledziewska et al 2015). Their analyses confirmed that low-pass WGS data sets are appropriate for genetic association studies, to create imputation panels, or to ask population genetics questions that are specific to these populations.…”

Section: Introductionmentioning

confidence: 63%

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Whole-genome sequencing in French Canadians from Quebec

Low‐Kam

Rhainds

et al. 2016

Hum Genet

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Genome-wide association studies (GWAS) have had a tremendous success in the identification of common DNA sequence variants associated with complex human diseases and traits. However, because of their design, GWAS are largely inappropriate to characterize the role of rare and low-frequency DNA variants on human phenotypic variation. Rarer genetic variation is geographically more restricted, supporting the need for local whole-genome sequencing (WGS) efforts to study these variants in specific populations. Here, we present the first large-scale low-pass WGS of the French-Canadian population. Specifically, we sequenced at ~5.6× coverage the whole genome of 1970 French Canadians recruited by the Montreal Heart Institute Biobank and identified 29 million bi-allelic variants (31 % novel), including 19 million variants with a minor allele frequency (MAF) <0.5 %. Genotypes from the WGS data are highly concordant with genotypes obtained by exome array on the same individuals (99.8 %), even when restricting this analysis to rare variants (MAF <0.5, 99.9 %) or heterozygous sites (98.9 %). To further validate our data set, we showed that we can effectively use it to replicate several genetic associations with myocardial infarction risk and blood lipid levels. Furthermore, we analyze the utility of our WGS data set to generate a French-Canadian-specific imputation reference panel and to infer population structure in the Province of Quebec. Our results illustrate the value of low-pass WGS to study the genetics of human diseases in the founder French-Canadian population.

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Section: Discussionsupporting

confidence: 78%

Section: Introductionmentioning

confidence: 63%

Whole-genome sequencing in French Canadians from Quebec

Low‐Kam

Rhainds

et al. 2016

Hum Genet

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“…genomics | noncoding genome | human genetic diversity R ecent technological advances have allowed for the largescale sequencing of the whole human genome (1)(2)(3)(4)(5)(6)(7). Most studies generated population-based information on human diversity using low to intermediate coverage of the genome (4× to 20× sequencing depth).…”

mentioning

confidence: 99%

Deep sequencing of 10,000 human genomes

Telenti

Pierce

Biggs

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

312

202

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We report on the sequencing of 10,545 human genomes at 30×-40× coverage with an emphasis on quality metrics and novel variant and sequence discovery. We find that 84% of an individual human genome can be sequenced confidently. This high-confidence region includes 91.5% of exon sequence and 95.2% of known pathogenic variant positions. We present the distribution of over 150 million single-nucleotide variants in the coding and noncoding genome. Each newly sequenced genome contributes an average of 8,579 novel variants. In addition, each genome carries on average 0.7 Mb of sequence that is not found in the main build of the hg38 reference genome. The density of this catalog of variation allowed us to construct high-resolution profiles that define genomic sites that are highly intolerant of genetic variation. These results indicate that the data generated by deep genome sequencing is of the quality necessary for clinical use.genomics | noncoding genome | human genetic diversity

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“…deCODE is studying rare variation at the population level in Iceland, using whole genome sequencing in a subset, augmented with genotype imputation in a larger sample (Gudbjartsson et al 2015). Analogous efforts are underway in Ashkenazi (Carmi et al 2014), Sardinian (Sidore et al 2015), Dutch (Genome of the Netherlands Consortium 2014), and Amish population samples (Crawford et al 2014). A consortium of researchers led by the NIMH is currently developing a whole genome reference panel for use in Anabaptist populations, which include Amish and Mennonites (Hou et al 2015).…”

Section: Characteristics Of Isolated Populationsmentioning

confidence: 99%

Finding Rare, Disease-Associated Variants in Isolated Groups: Potential Advantages of Mennonite Populations

Lopes¹,

Hou²,

Boldt³

et al. 2016

Human Biology

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Large-scale genotyping and next generation sequencing techniques have allowed great advances in the field of molecular genetics. Numerous common variants of low impact have been associated with many complex human traits and diseases, such as bipolar disorder and schizophrenia. Although they may exert a greater impact on risk, few rare disease variants have been found, owing to the greatly increased sample sizes that are typically necessary to demonstrate association with rarer variants. One alternative strategy is to study isolated populations, where historical bottlenecks reduce genetic diversity and some otherwise rare variants may drift to higher frequencies. Here we describe the Mennonite population settlements, considering their history of multiple bottlenecks followed by demographic expansion and a currently widespread geographical distribution. We argue that Mennonite populations are valuable partners for studies seeking to find genetic variants that exert a high impact on risk for a variety of common disorders, including mental illnesses.

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Genome sequencing elucidates Sardinian genetic architecture and augments association analyses for lipid and blood inflammatory markers

Cited by 224 publications

References 77 publications

Whole-genome sequencing in French Canadians from Quebec

Whole-genome sequencing in French Canadians from Quebec

Deep sequencing of 10,000 human genomes

Finding Rare, Disease-Associated Variants in Isolated Groups: Potential Advantages of Mennonite Populations

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