Genetic population structure across Brittany and the downstream Loire basin provides new insights on the demographic history of Western Europe

Alves, Isabel; Giemza, Joanna; Blum, Michaël G. B.; Bernhardsson, Carolina; Chatel, Stéphanie; Karakachoff, Matilde; Pierre, Aude Saint; Herzig, Anthony F.; Olaso, Robert; Monteil, Martial; Gallien, Véronique; Cabot, Élodie; Svensson, Emma; Daian, Delphine; Baron, Estelle; Berthellier, Charlotte; Besse, Céline; Blanché, Hélène; Bocher, Ozvan; Boland, Anne; Bonnaud, Stéphanie; Charpentier, Eric; Dandine‐Roulland, Claire; Férec, Claude; Fruchet, Christine; Lecointe, Simon; Floch, Édith Le; Ludwig, Thomas; Marenne, Gaëlle; Meyer, Vincent; Quellery, Elisabeth; Racimo, Fernando; Rouault, Karen; Sandron, Florian; Schott, Jean‐Jacques; Suarez, Lourdes Velo; Violleau, Jade; Willerslev, Eske; Coativy, Yves; Jézéquel, Mael; Bris, Daniel Le; Nicolas, Clément; Pailler, Yvan; Goldberg, Marcel; Zins, Marie; Marec, Hervé Le; Jakobsson, Mattias; Darlu, Pierre; Génin, Emmanuelle; Deleuze, Jean‐François; Redon, Richard; Dina, Christian

doi:10.1101/2022.02.03.478491

Cited by 7 publications

(8 citation statements)

References 92 publications

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“…Imputation accuracy has not been investigated in French populations. The French population has considerable internal diversity 31,32 and does not have direct representations in panels such as 1000G, HRC, or TOPMED. Recently, 856 French individuals were whole-genome sequenced at 30-40×, this makes up the FranceGenRef panel (Labex GENMED http://www.genmed.fr/); an obvious candidate for an imputation panel for French genomes.…”

Section: Introductionmentioning

confidence: 99%

Can imputation in a European country be improved by local reference panels? The example of France

Herzig

Velo‐Suárez

Dina³

et al. 2022

Preprint

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France has a population with extensive internal fine-structure; and while public imputation reference panels contain an abundance of European genomes, there include few French genomes. Intuitively, using a ‘study specific panel’ (SSP) for France would therefore likely be beneficial. To investigate, we imputed 550 French individuals using either the University of Michigan imputation server with the Haplotype Reference Consortium panel, or in-house using an SSP of 850 whole-genome sequenced French individuals.With approximate geo-localization of both our target and SSP individuals we are able to pinpoint different scenarios where SSP-based imputation would be preferred over server-based imputation or vice-versa. We could also show to a high degree of resolution how the proximity of the reference panel to a target individual determined the accuracy of both haplotype phasing and genotype imputation.Previous comparisons of different strategies have shown the benefits of combining public reference panels with SSPs. Getting the best out of both resources simultaneously is unfortunately impractical. We put forward a pragmatic solution where server-based and SSP-based imputation outcomes can be combined based on comparing posterior genotype probabilities. Such an approach can give a level of imputation accuracy markedly in excess of what could be achieved with either strategy alone.

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Section: Introductionmentioning

confidence: 99%

Can imputation in a European country be improved by local reference panels? The example of France

Herzig

Velo‐Suárez

Dina³

et al. 2022

Preprint

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“…Fluorescence intensities were obtained from Precision Medicine Research Array (PMRA - Affymetrix) and quantified by Affymetrix GeneTitan Multi-Channel Instrument. Genotypes were merged with PREGO control population 46 and SNPs with MAF<10%, call rate < 95% or p<1.10-5 when testing for Hardy-Weinberg equilibrium were excluded. IBD regions were then identified using IBDLD v3.34 with noLD method.…”

Section: Methodsmentioning

confidence: 99%

Identification of rare missense variants reducing cathepsin O secretion in families with intracranial aneurysm

Freneau

Blanchet

Benichi

et al. 2023

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Background: Intracranial aneurysm (IA) is a common cerebrovascular abnormality characterized by localized dilation and wall thinning in intracranial arteries, that frequently leads to fatal vascular rupture. The mechanisms underlying IA formation, growth and rupture are mostly unknown, and while increasing evidence suggest a genetic component of IA, identification of specific genes or causal molecular pathways remains largely inconclusive and only a small fraction of the risk attributable to genetics for IA in the general population. Methods: Here, we combined whole exome sequencing and identity-by -descent analyses with functional investigations to identify rare IA predisposing variants in familial forms of IA and understand their contribution to the pathophysiology of IA. Results: We identified two rare missense variants in the CTSO gene shared by all the affected relatives in two large pedigrees with multiple IA-affected relative. CTSO encodes for the cysteine-type papain-like cathepsin CTSO. Functional analyses revealed that CTSO acts as an extracellular protease controlling vascular smooth muscle cell migration and adhesion to the extracellular matrix. CTSO depletion, as well as expression of the two CTSO variants, which were poorly secreted, led to increase the amount of fibronectin. This effect is associated with a marked increase in VSMC stiffness which was rescued by exogenous CTSO. Conclusions: This report identifies rare CTSO variants in familial IA patients and suggests that the increased susceptibility to IA induced by these variants is likely related to their primary effects on the vascular tissue, and more particularly on the media layer of the wall of cerebral arteries.

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“…Note that there is an implicit assumption that the two haplotypes within an individual on the control panel share a relatively similar ancestry -in the context of our study, this is reasonable for the 1000G individuals and is also respected by the FranceGenRef panel by design [47][48][49]. This is because the individuals of FranceGenRef were recruited based on grand-parent birthplace data taking individuals with all four grand-parents born within a small locality hence approximately insuring that such individuals have both maternal and paternal haplotypes from a similar region.…”

Section: The Surfbat Approachmentioning

confidence: 99%

“…We demonstrate the properties of SURFBAT through simulation using the 1000 Genomes project [47] (1000G) and data from 856 individuals with Whole Genome Sequencing (WGS) data from the FranceGenRef project [48,49] (FGR). This is followed by a demonstration using true data from 346 case individuals diagnosed with Brugada syndrome [50].…”

Section: Introductionmentioning

confidence: 99%

SURFBAT: a surrogate family-based association test building on large imputation reference panels

Herzig

Rubinacci

Marenne

et al. 2023

Preprint

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Genotype-phenotype association tests are typically adjusted for population stratification using principal components that are estimated genome-wide. This lacks resolution when analysing populations with fine structure and/or individuals with fine levels of admixture. This can affect power and precision, and is a particularly relevant consideration when control individuals are recruited using geographic selection criteria. Such is the case in France where we have recently created reference panels of individuals anchored to different geographic regions. To make correct comparisons against case groups, who would likely be gathered from large urban areas, new methods are needed. We present SURFBAT (a SURrogate Family Based Association Test) which performs an approximation of the transmission-disequilibrium test. Our method hinges on the application of genotype imputation algorithms to match similar haplotypes between the case and control groups. This permits us to approximate local ancestry informed posterior probabilities of un-transmitted parental alleles of each case individual. SURFBAT provides an association test that is inherently robust to fine-scale population stratification and opens up the possibility of efficiently using large imputation reference panels as control groups for association testing. The method is suitable when the control panel spans the local ancestry spectrum of the case-group population and each control has similar paternal and maternal ancestries. This is the case for our reference panels where individuals have their four grand-parents born in the same geographic area. In contrast to other methods for association testing that incorporate local-ancestry inference, SURFBAT does not require a set of ancestry groups to be defined, nor for local ancestry to be explicitly estimated. We demonstrate the interest of our tool on simulated datasets created from the 1000 Genomes project and the FranceGenRef project, as well as on a real-data example for a group of case individuals affected by Brugada syndrome.

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Genetic population structure across Brittany and the downstream Loire basin provides new insights on the demographic history of Western Europe

Cited by 7 publications

References 92 publications

Can imputation in a European country be improved by local reference panels? The example of France

Can imputation in a European country be improved by local reference panels? The example of France

Identification of rare missense variants reducing cathepsin O secretion in families with intracranial aneurysm

SURFBAT: a surrogate family-based association test building on large imputation reference panels

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