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Article ; Online: Controlling for human population stratification in rare variant association studies

Matthieu Bouaziz / Jimmy Mullaert / Benedetta Bigio / Yoann Seeleuthner / Jean-Laurent Casanova / Alexandre Alcais / Laurent Abel / Aurélie Cobat

Scientific Reports, Vol 11, Iss 1, Pp 1-

2021 Volume 14

Abstract: Abstract Population stratification is a confounder of genetic association studies. In analyses of rare variants, corrections based on principal components (PCs) and linear mixed models (LMMs) yield conflicting conclusions. Studies evaluating these ... ...

Abstract	Abstract Population stratification is a confounder of genetic association studies. In analyses of rare variants, corrections based on principal components (PCs) and linear mixed models (LMMs) yield conflicting conclusions. Studies evaluating these approaches generally focused on limited types of structure and large sample sizes. We investigated the properties of several correction methods through a large simulation study using real exome data, and several within- and between-continent stratification scenarios. We considered different sample sizes, with situations including as few as 50 cases, to account for the analysis of rare disorders. Large samples showed that accounting for stratification was more difficult with a continental than with a worldwide structure. When considering a sample of 50 cases, an inflation of type-I-errors was observed with PCs for small numbers of controls (≤ 100), and with LMMs for large numbers of controls (≥ 1000). We also tested a novel local permutation method (LocPerm), which maintained a correct type-I-error in all situations. Powers were equivalent for all approaches pointing out that the key issue is to properly control type-I-errors. Finally, we found that power of analyses including small numbers of cases can be increased, by adding a large panel of external controls, provided an appropriate stratification correction was used.
Keywords	Medicine ; R ; Science ; Q
Subject code	310
Language	English
Publishing date	2021-09-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Disentangling Inborn and Acquired Immunity in Human Twins

Casanova, Jean-Laurent / Laurent Abel

Cell. 2015 Jan. 15, v. 160

2015

Abstract: The human geneticist Archibald Garrod noted in 1931 that, âIt is, of necessity, no easy matter toÂ distinguish between immunity which is inborn and that which has been acquiredâ (The Inborn Factors in Disease). In this issue of Cell, Brodin etÂ al. ... ...

Abstract	The human geneticist Archibald Garrod noted in 1931 that, âIt is, of necessity, no easy matter toÂ distinguish between immunity which is inborn and that which has been acquiredâ (The Inborn Factors in Disease). In this issue of Cell, Brodin etÂ al. show that the heritability of blood counts rapidly decreases with age for the lymphoid subsets responsible for adaptive immunity, unlike cells from other hematopoietic lineages.
Keywords	adaptive immunity ; blood ; geneticists ; heritability ; humans ; twins
Language	English
Dates of publication	2015-0115
Size	p. 13-15.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2014.12.029
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Genetic adaptation to pathogens and increased risk of inflammatory disorders in post-Neolithic Europe

Gaspard Kerner / Anna-Lena Neehus / Quentin Philippot / Jonathan Bohlen / Darawan Rinchai / Nacim Kerrouche / Anne Puel / Shen-Ying Zhang / Stéphanie Boisson-Dupuis / Laurent Abel / Jean-Laurent Casanova / Etienne Patin / Guillaume Laval / Lluis Quintana-Murci

Cell Genomics, Vol 3, Iss 2, Pp 100248- (2023)

2023

Abstract: Summary: Ancient genomics can directly detect human genetic adaptation to environmental cues. However, it remains unclear how pathogens have exerted selective pressures on human genome diversity across different epochs and affected present-day ... ...

Abstract	Summary: Ancient genomics can directly detect human genetic adaptation to environmental cues. However, it remains unclear how pathogens have exerted selective pressures on human genome diversity across different epochs and affected present-day inflammatory disease risk. Here, we use an ancestry-aware approximate Bayesian computation framework to estimate the nature, strength, and time of onset of selection acting on 2,879 ancient and modern European genomes from the last 10,000 years. We found that the bulk of genetic adaptation occurred after the start of the Bronze Age, <4,500 years ago, and was enriched in genes relating to host-pathogen interactions. Furthermore, we detected directional selection acting on specific leukocytic lineages and experimentally demonstrated that the strongest negatively selected candidate variant in immunity genes, lipopolysaccharide-binding protein (LBP) D283G, is hypomorphic. Finally, our analyses suggest that the risk of inflammatory disorders has increased in post-Neolithic Europeans, possibly because of antagonistic pleiotropy following genetic adaptation to pathogens.
Keywords	ancient DNA ; immunity ; host defense ; natural selection ; local adaptation ; inflammatory disorders ; Genetics ; QH426-470 ; Internal medicine ; RC31-1245
Subject code	930
Language	English
Publishing date	2023-02-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Deep resequencing identifies candidate functional genes in leprosy GWAS loci.

Vinicius M Fava / Monica Dallmann-Sauer / Marianna Orlova / Wilian Correa-Macedo / Nguyen Van Thuc / Vu Hong Thai / Alexandre Alcaïs / Laurent Abel / Aurélie Cobat / Erwin Schurr

PLoS Neglected Tropical Diseases, Vol 15, Iss 12, p e

2021 Volume 0010029

Abstract: Leprosy is the second most prevalent mycobacterial disease globally. Despite the existence of an effective therapy, leprosy incidence has consistently remained above 200,000 cases per year since 2010. Numerous host genetic factors have been identified ... ...

Abstract	Leprosy is the second most prevalent mycobacterial disease globally. Despite the existence of an effective therapy, leprosy incidence has consistently remained above 200,000 cases per year since 2010. Numerous host genetic factors have been identified for leprosy that contribute to the persistently high case numbers. In the past decade, genetic epidemiology approaches, including genome-wide association studies (GWAS), identified more than 30 loci contributing to leprosy susceptibility. However, GWAS loci commonly encompass multiple genes, which poses a challenge to define causal candidates for each locus. To address this problem, we hypothesized that genes contributing to leprosy susceptibility differ in their frequencies of rare protein-altering variants between cases and controls. Using deep resequencing we assessed protein-coding variants for 34 genes located in GWAS or linkage loci in 555 Vietnamese leprosy cases and 500 healthy controls. We observed 234 nonsynonymous mutations in the targeted genes. A significant depletion of protein-altering variants was detected for the IL18R1 and BCL10 genes in leprosy cases. The IL18R1 gene is clustered with IL18RAP and IL1RL1 in the leprosy GWAS locus on chromosome 2q12.1. Moreover, in a recent GWAS we identified an HLA-independent signal of association with leprosy on chromosome 6p21. Here, we report amino acid changes in the CDSN and PSORS1C2 genes depleted in leprosy cases, indicating them as candidate genes in the chromosome 6p21 locus. Our results show that deep resequencing can identify leprosy candidate susceptibility genes that had been missed by classic linkage and association approaches.
Keywords	Arctic medicine. Tropical medicine ; RC955-962 ; Public aspects of medicine ; RA1-1270
Subject code	572
Language	English
Publishing date	2021-12-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Reprogramming of Amino Acid Metabolism Differs between Community-Acquired Pneumonia and Infection-Associated Exacerbation of Chronic Obstructive Pulmonary Disease

Haroon Arshad / Anastasios Siokis / Raimo Franke / Aamna Habib / Juan Carlos López Alfonso / Yuliya Poliakova / Eva Lücke / Katina Michaelis / Mark Brönstrup / Michael Meyer-Hermann / Ursula Bilitewski / Jordi Vila / Laurent Abel / Thomas Illig / Jens Schreiber / Frank Pessler

Cells, Vol 11, Iss 2283, p

2022 Volume 2283

Abstract: Amino acids and their metabolites are key regulators of immune responses, and plasma levels may change profoundly during acute disease states. Using targeted metabolomics, we evaluated concentration changes in plasma amino acids and related metabolites ... ...

Abstract	Amino acids and their metabolites are key regulators of immune responses, and plasma levels may change profoundly during acute disease states. Using targeted metabolomics, we evaluated concentration changes in plasma amino acids and related metabolites in community-acquired pneumonia (CAP, n = 29; compared against healthy controls, n = 33) from presentation to hospital through convalescence. We further aimed to identify biomarkers for acute CAP vs. the clinically potentially similar infection-triggered COPD exacerbation ( n = 13). Amino acid metabolism was globally dysregulated in both CAP and COPD. Levels of most amino acids were markedly depressed in acute CAP, and total amino acid concentrations on admission were an accurate biomarker for the differentiation from COPD (AUC = 0.93), as were reduced asparagine and threonine levels (both AUC = 0.92). Reduced tryptophan and histidine levels constituted the most accurate biomarkers for acute CAP vs. controls (AUC = 0.96, 0.94). Only kynurenine, symmetric dimethyl arginine, and phenylalanine levels were increased in acute CAP, and the kynurenine/tryptophan ratio correlated best with clinical recovery and resolution of inflammation. Several amino acids did not reach normal levels by the 6-week follow-up. Glutamate levels were reduced on admission but rose during convalescence to 1.7-fold above levels measured in healthy control. Our data suggest that dysregulated amino acid metabolism in CAP partially persists through clinical recovery and that amino acid metabolism constitutes a source of promising biomarkers for CAP. In particular, total amino acids, asparagine, and threonine may constitute plasma biomarker candidates for the differentiation between CAP and infection-triggered COPD exacerbation and, perhaps, the detection of pneumonia in COPD.
Keywords	amino acids ; biogenic amines ; biomarkers ; chronic obstructive pulmonary disease ; diagnosis ; inflammation ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2022-07-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Allele-dependent interaction of LRRK2 and NOD2 in leprosy.

Monica Dallmann-Sauer / Yong Zhong Xu / Ana Lúcia França da Costa / Shao Tao / Tiago Araujo Gomes / Rhana Berto da Silva Prata / Wilian Correa-Macedo / Jérémy Manry / Alexandre Alcaïs / Laurent Abel / Aurélie Cobat / Vinicius M Fava / Roberta Olmo Pinheiro / Flavio Alves Lara / Christian M Probst / Marcelo T Mira / Erwin Schurr

PLoS Pathogens, Vol 19, Iss 3, p e

2023 Volume 1011260

Abstract: Leprosy, caused by Mycobacterium leprae, rarely affects children younger than 5 years. Here, we studied a multiplex leprosy family that included monozygotic twins aged 22 months suffering from paucibacillary leprosy. Whole genome sequencing identified ... ...

Abstract	Leprosy, caused by Mycobacterium leprae, rarely affects children younger than 5 years. Here, we studied a multiplex leprosy family that included monozygotic twins aged 22 months suffering from paucibacillary leprosy. Whole genome sequencing identified three amino acid mutations previously associated with Crohn's disease and Parkinson's disease as candidate variants for early onset leprosy: LRRK2 N551K, R1398H and NOD2 R702W. In genome-edited macrophages, we demonstrated that cells expressing the LRRK2 mutations displayed reduced apoptosis activity following mycobacterial challenge independently of NOD2. However, employing co-immunoprecipitation and confocal microscopy we showed that LRRK2 and NOD2 proteins interacted in RAW cells and monocyte-derived macrophages, and that this interaction was substantially reduced for the NOD2 R702W mutation. Moreover, we observed a joint effect of LRRK2 and NOD2 variants on Bacillus Calmette-Guérin (BCG)-induced respiratory burst, NF-κB activation and cytokine/chemokine secretion with a strong impact for the genotypes found in the twins consistent with a role of the identified mutations in the development of early onset leprosy.
Keywords	Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
Subject code	616
Language	English
Publishing date	2023-03-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Genome-wide association study of Buruli ulcer in rural Benin highlights role of two LncRNAs and the autophagy pathway

Jeremy Manry / Quentin B. Vincent / Christian Johnson / Maya Chrabieh / Lazaro Lorenzo / Ioannis Theodorou / Marie-Françoise Ardant / Estelle Marion / Annick Chauty / Laurent Marsollier / Laurent Abel / Alexandre Alcaïs

Communications Biology, Vol 3, Iss 1, Pp 1-

2020 Volume 10

Abstract: Jeremy Manry, Quentin Vincent et al. report a genome-wide association study for susceptibility to Buruli ulcer in a rural population from the West African country of Benin. They identify two independently associated variants within LncRNA genes and ... ...

Abstract	Jeremy Manry, Quentin Vincent et al. report a genome-wide association study for susceptibility to Buruli ulcer in a rural population from the West African country of Benin. They identify two independently associated variants within LncRNA genes and confirm the protective effect of a missense variant in the bacterial autophagy gene ATG16L1.
Keywords	Biology (General) ; QH301-705.5
Language	English
Publishing date	2020-04-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Family-based genome-wide association study of leprosy in Vietnam.

Chaima Gzara / Monica Dallmann-Sauer / Marianna Orlova / Nguyen Van Thuc / Vu Hong Thai / Vinicius M Fava / Marie-Thérèse Bihoreau / Anne Boland / Laurent Abel / Alexandre Alcaïs / Erwin Schurr / Aurélie Cobat

PLoS Pathogens, Vol 16, Iss 5, p e

2020 Volume 1008565

Abstract: Leprosy is a chronic infectious disease of the skin and peripheral nerves with a strong genetic predisposition. Recent genome-wide approaches have identified numerous common variants associated with leprosy, almost all in the Chinese population. We ... ...

Abstract	Leprosy is a chronic infectious disease of the skin and peripheral nerves with a strong genetic predisposition. Recent genome-wide approaches have identified numerous common variants associated with leprosy, almost all in the Chinese population. We conducted the first family-based genome-wide association study of leprosy in 622 affected offspring from Vietnam, followed by replication in an independent sample of 1181 leprosy cases and 668 controls of the same ethnic origin. The most significant results were observed within the HLA region, in which six SNPs displayed genome-wide significant associations, all of which were replicated in the independent case/control sample. We investigated the signal in the HLA region in more detail, by conducting a multivariate analysis on the case/control sample of 319 GWAS-suggestive HLA hits for which evidence for replication was obtained. We identified three independently associated SNPs, two located in the HLA class I region (rs1265048: OR = 0.69 [0.58-0.80], combined p-value = 5.53x10-11; and rs114598080: OR = 1.47 [1.46-1.48], combined p-value = 8.77x10-13), and one located in the HLA class II region (rs3187964 (OR = 1.67 [1.55-1.80], combined p-value = 8.35x10-16). We also validated two previously identified risk factors for leprosy: the missense variant rs3764147 in the LACC1 gene (OR = 1.52 [1.41-1.63], combined p-value = 5.06x10-14), and the intergenic variant rs6871626 located close to the IL12B gene (OR = 0.73 [0.61-0.84], combined p-value = 6.44x10-8). These results shed new light on the genetic control of leprosy, by dissecting the influence of HLA SNPs, and validating the independent role of two additional variants in a large Vietnamese sample.
Keywords	Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
Subject code	570 ; 616
Language	English
Publishing date	2020-05-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The complex pattern of genetic associations of leprosy with HLA class I and class II alleles can be reduced to four amino acid positions.

Monica Dallmann-Sauer / Vinicius M Fava / Chaïma Gzara / Marianna Orlova / Nguyen Van Thuc / Vu Hong Thai / Alexandre Alcaïs / Laurent Abel / Aurélie Cobat / Erwin Schurr

PLoS Pathogens, Vol 16, Iss 8, p e

2020 Volume 1008818

Abstract: Leprosy is a chronic disease caused by Mycobacterium leprae. Worldwide, more than 200,000 new patients are affected by leprosy annually, making it the second most common mycobacterial disease after tuberculosis. The MHC/HLA region has been consistently ... ...

Abstract	Leprosy is a chronic disease caused by Mycobacterium leprae. Worldwide, more than 200,000 new patients are affected by leprosy annually, making it the second most common mycobacterial disease after tuberculosis. The MHC/HLA region has been consistently identified as carrying major leprosy susceptibility variants in different populations at times with inconsistent results. To establish the unambiguous molecular identity of classical HLA class I and class II leprosy susceptibility factors, we applied next-generation sequencing to genotype with high-resolution 11 HLA class I and class II genes in 1,155 individuals from a Vietnamese leprosy case-control sample. HLA alleles belonging to an extended haplotype from HLA-A to HLA-DPB1 were associated with risk to leprosy. This susceptibility signal could be reduced to the HLA-DRB110:01~ HLA-DQA101:05 alleles which were in complete linkage disequilibrium (LD). In addition, haplotypes containing HLA-DRB3~ HLA-DRB112:02 and HLA-C07:06~ HLA-B44:03~ HLA-DRB107:01 alleles were found as two independent protective factors for leprosy. Moreover, we replicated the previously associated HLA-DRB115:01 as leprosy risk factor and HLA-DRB104:05~HLA-DQA1*03:03 as protective alleles. When we narrowed the analysis to the single amino acid level, we found that the associations of the HLA alleles were largely captured by four independent amino acids at HLA-DRβ1 positions 57 (D) and 13 (F), HLA-B position 63 (E) and HLA-A position 19 (K). Hence, analyses at the amino acid level circumvented the ambiguity caused by strong LD of leprosy susceptibility HLA alleles and identified four distinct leprosy susceptibility factors.
Keywords	Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2020-08-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Genetic Epidemiology of Infectious Diseases in Humans

Laurent Abel / Alain J. Dessein

Emerging Infectious Diseases, Vol 4, Iss 4, Pp 593-

Design of Population- Based Studies

1998 Volume 603

Abstract: The spread and clinical manifestations of an infection in human populations depend on a variety of factors, among them host genetics. Familial linkage studies used in genetic epidemiology to identify host genes test for nonrandom segregation of a trait ... ...

Abstract	The spread and clinical manifestations of an infection in human populations depend on a variety of factors, among them host genetics. Familial linkage studies used in genetic epidemiology to identify host genes test for nonrandom segregation of a trait with a few candidate chromosomal regions or any regions in the genome (genomewide search). When a clear major gene model can be inferred and reliable epidemiologic information is collected (e.g., in schistosomiasis), parametric linkage studies are used. When the genetic model cannot be defined (e.g., in leprosy and malaria), nonparametric linkage studies (e.g., sibling-pair studies) are recommended. Once evidence of linkage is obtained, the gene can be identified by polymorphisms strongly associated with the trait. When the tested polymorphism is in strong linkage disequilibrium with the disease allele or is the disease allele itself (e.g., in HIV infection and malaria), association studies can directly identify the disease gene. Finally, the role of the detected polymorphism in causing the trait is validated by functional studies.
Keywords	France ; Madagascar ; Senegal ; Medicine ; R ; Infectious and parasitic diseases ; RC109-216
Subject code	630
Language	English
Publishing date	1998-12-01T00:00:00Z
Publisher	Centers for Disease Control and Prevention
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