A Genomewide Search Using an Original Pairwise Sampling Approach for Large Genealogies Identifies a New Locus for Total and Low-Density Lipoprotein Cholesterol in Two Genetically Differentiated Isolates of Sardinia

Mario Falchi; Paola Forabosco; Evelina Mocci; Cesare Cappio Borlino; Andrea Picciau; Emanuela Virdis; Ivana Persico; Debora Parracciani; Andrea Angius; Mario Pirastu

doi:10.1086/426155

A Genomewide Search Using an Original Pairwise Sampling Approach for Large Genealogies Identifies a New Locus for Total and Low-Density Lipoprotein Cholesterol in Two Genetically Differentiated Isolates of Sardinia

Mario Falchi, Paola Forabosco, Evelina Mocci, Cesare Cappio Borlino, Andrea Picciau, Emanuela Virdis, Ivana Persico, Debora Parracciani, Andrea Angius, Mario Pirastu

Research output: Contribution to journal › Article › peer-review

46 Citations (Scopus)

Abstract

A powerful approach to mapping the genes for complex traits is to study isolated founder populations, in which genetic heterogeneity and environmental noise are likely to be reduced and in which extended genealogical data are often available. Using graph theory, we applied an approach that involved sampling from the large number of pairwise relationships present in an extended genealogy to reconstruct sets of subpedigrees that maximize the useful information for linkage mapping while minimizing calculation burden. We investigated, through simulation, the properties of the different sets in terms of bias in identity-by-descent (IBD) estimation and power decrease under various genetic models. We applied this approach to a small isolated population from Sardinia, the village of Talana, consisting of a unique large and complex pedigree, and performed a genomewide search through variance-components linkage analysis for serum lipid levels. We identified a region of significant linkage on chromosome 2 for total serum cholesterol and low-density lipoprotein (LDL) cholesterol. Through higher-density mapping, we obtained an increased linkage for both traits on 2q21.2-q24.1, with a LOD score of 4.3 for total serum cholesterol and of 3.9 for LDL cholesterol. A replication study was performed in an independent and larger set from a genetically differentiated isolated population of the same region of Sardinia, the village of Perdasdefogu. We obtained consistent linkage to the region for total serum cholesterol (LOD score 1.4) and LDL cholesterol (LOD score 2.2), with a level of concordance uncommon for complex traits, and refined the location of the quantitative-trait locus. Interestingly, the 2q21.1-22 region has also been linked to premature coronary heart disease in Finns, and, in the adjacent 2q14 region, significant linkage with triglycerides has been reported in Hutterites.

Original language	English
Pages (from-to)	1015-1031
Number of pages	17
Journal	American Journal of Human Genetics
Volume	75
Issue number	6
DOIs	https://doi.org/10.1086/426155
Publication status	Published - Dec 2004

Keywords

Cholesterol
Cholesterol, LDL
Chromosome Mapping
Chromosomes, Human, Pair 2
Computer Simulation
Genome, Human
Genotype
Humans
Italy
Linear Models
Lod Score
Pedigree
Quantitative Trait Loci

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Falchi, M., Forabosco, P., Mocci, E., Borlino, C. C., Picciau, A., Virdis, E., Persico, I., Parracciani, D., Angius, A., & Pirastu, M. (2004). A Genomewide Search Using an Original Pairwise Sampling Approach for Large Genealogies Identifies a New Locus for Total and Low-Density Lipoprotein Cholesterol in Two Genetically Differentiated Isolates of Sardinia. American Journal of Human Genetics, 75(6), 1015-1031. https://doi.org/10.1086/426155

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title = "A Genomewide Search Using an Original Pairwise Sampling Approach for Large Genealogies Identifies a New Locus for Total and Low-Density Lipoprotein Cholesterol in Two Genetically Differentiated Isolates of Sardinia",

abstract = "A powerful approach to mapping the genes for complex traits is to study isolated founder populations, in which genetic heterogeneity and environmental noise are likely to be reduced and in which extended genealogical data are often available. Using graph theory, we applied an approach that involved sampling from the large number of pairwise relationships present in an extended genealogy to reconstruct sets of subpedigrees that maximize the useful information for linkage mapping while minimizing calculation burden. We investigated, through simulation, the properties of the different sets in terms of bias in identity-by-descent (IBD) estimation and power decrease under various genetic models. We applied this approach to a small isolated population from Sardinia, the village of Talana, consisting of a unique large and complex pedigree, and performed a genomewide search through variance-components linkage analysis for serum lipid levels. We identified a region of significant linkage on chromosome 2 for total serum cholesterol and low-density lipoprotein (LDL) cholesterol. Through higher-density mapping, we obtained an increased linkage for both traits on 2q21.2-q24.1, with a LOD score of 4.3 for total serum cholesterol and of 3.9 for LDL cholesterol. A replication study was performed in an independent and larger set from a genetically differentiated isolated population of the same region of Sardinia, the village of Perdasdefogu. We obtained consistent linkage to the region for total serum cholesterol (LOD score 1.4) and LDL cholesterol (LOD score 2.2), with a level of concordance uncommon for complex traits, and refined the location of the quantitative-trait locus. Interestingly, the 2q21.1-22 region has also been linked to premature coronary heart disease in Finns, and, in the adjacent 2q14 region, significant linkage with triglycerides has been reported in Hutterites.",

keywords = "Cholesterol, Cholesterol, LDL, Chromosome Mapping, Chromosomes, Human, Pair 2, Computer Simulation, Genome, Human, Genotype, Humans, Italy, Linear Models, Lod Score, Pedigree, Quantitative Trait Loci",

author = "Mario Falchi and Paola Forabosco and Evelina Mocci and Borlino, {Cesare Cappio} and Andrea Picciau and Emanuela Virdis and Ivana Persico and Debora Parracciani and Andrea Angius and Mario Pirastu",

year = "2004",

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Falchi, M , Forabosco, P, Mocci, E, Borlino, CC, Picciau, A, Virdis, E, Persico, I, Parracciani, D, Angius, A & Pirastu, M 2004, 'A Genomewide Search Using an Original Pairwise Sampling Approach for Large Genealogies Identifies a New Locus for Total and Low-Density Lipoprotein Cholesterol in Two Genetically Differentiated Isolates of Sardinia', American Journal of Human Genetics, vol. 75, no. 6, pp. 1015-1031. https://doi.org/10.1086/426155

A Genomewide Search Using an Original Pairwise Sampling Approach for Large Genealogies Identifies a New Locus for Total and Low-Density Lipoprotein Cholesterol in Two Genetically Differentiated Isolates of Sardinia. / Falchi, Mario ; Forabosco, Paola; Mocci, Evelina et al.
In: American Journal of Human Genetics, Vol. 75, No. 6, 12.2004, p. 1015-1031.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - A Genomewide Search Using an Original Pairwise Sampling Approach for Large Genealogies Identifies a New Locus for Total and Low-Density Lipoprotein Cholesterol in Two Genetically Differentiated Isolates of Sardinia

AU - Falchi, Mario

AU - Forabosco, Paola

AU - Mocci, Evelina

AU - Borlino, Cesare Cappio

AU - Picciau, Andrea

AU - Virdis, Emanuela

AU - Persico, Ivana

AU - Parracciani, Debora

AU - Angius, Andrea

AU - Pirastu, Mario

PY - 2004/12

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N2 - A powerful approach to mapping the genes for complex traits is to study isolated founder populations, in which genetic heterogeneity and environmental noise are likely to be reduced and in which extended genealogical data are often available. Using graph theory, we applied an approach that involved sampling from the large number of pairwise relationships present in an extended genealogy to reconstruct sets of subpedigrees that maximize the useful information for linkage mapping while minimizing calculation burden. We investigated, through simulation, the properties of the different sets in terms of bias in identity-by-descent (IBD) estimation and power decrease under various genetic models. We applied this approach to a small isolated population from Sardinia, the village of Talana, consisting of a unique large and complex pedigree, and performed a genomewide search through variance-components linkage analysis for serum lipid levels. We identified a region of significant linkage on chromosome 2 for total serum cholesterol and low-density lipoprotein (LDL) cholesterol. Through higher-density mapping, we obtained an increased linkage for both traits on 2q21.2-q24.1, with a LOD score of 4.3 for total serum cholesterol and of 3.9 for LDL cholesterol. A replication study was performed in an independent and larger set from a genetically differentiated isolated population of the same region of Sardinia, the village of Perdasdefogu. We obtained consistent linkage to the region for total serum cholesterol (LOD score 1.4) and LDL cholesterol (LOD score 2.2), with a level of concordance uncommon for complex traits, and refined the location of the quantitative-trait locus. Interestingly, the 2q21.1-22 region has also been linked to premature coronary heart disease in Finns, and, in the adjacent 2q14 region, significant linkage with triglycerides has been reported in Hutterites.

AB - A powerful approach to mapping the genes for complex traits is to study isolated founder populations, in which genetic heterogeneity and environmental noise are likely to be reduced and in which extended genealogical data are often available. Using graph theory, we applied an approach that involved sampling from the large number of pairwise relationships present in an extended genealogy to reconstruct sets of subpedigrees that maximize the useful information for linkage mapping while minimizing calculation burden. We investigated, through simulation, the properties of the different sets in terms of bias in identity-by-descent (IBD) estimation and power decrease under various genetic models. We applied this approach to a small isolated population from Sardinia, the village of Talana, consisting of a unique large and complex pedigree, and performed a genomewide search through variance-components linkage analysis for serum lipid levels. We identified a region of significant linkage on chromosome 2 for total serum cholesterol and low-density lipoprotein (LDL) cholesterol. Through higher-density mapping, we obtained an increased linkage for both traits on 2q21.2-q24.1, with a LOD score of 4.3 for total serum cholesterol and of 3.9 for LDL cholesterol. A replication study was performed in an independent and larger set from a genetically differentiated isolated population of the same region of Sardinia, the village of Perdasdefogu. We obtained consistent linkage to the region for total serum cholesterol (LOD score 1.4) and LDL cholesterol (LOD score 2.2), with a level of concordance uncommon for complex traits, and refined the location of the quantitative-trait locus. Interestingly, the 2q21.1-22 region has also been linked to premature coronary heart disease in Finns, and, in the adjacent 2q14 region, significant linkage with triglycerides has been reported in Hutterites.

KW - Cholesterol

KW - Cholesterol, LDL

KW - Chromosome Mapping

KW - Chromosomes, Human, Pair 2

KW - Computer Simulation

KW - Genome, Human

KW - Genotype

KW - Humans

KW - Italy

KW - Linear Models

KW - Lod Score

KW - Pedigree

KW - Quantitative Trait Loci

U2 - 10.1086/426155

DO - 10.1086/426155

M3 - Article

C2 - 15478097

SN - 0002-9297

VL - 75

SP - 1015

EP - 1031

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 6

ER -