Abecasis, Goncalo R.

Boehnke, Michael

Cucca, Francesco

Hveem, Kristian

Jackson, Anne U.

Kang, Hyun M.

Laakso, Markku

Lakka, Timo A.

Li, Bingshan

Maninchedda, Giuseppe

Mulas, Antonella

Nagaraja, Ramaiah

Njolstad, Inger

Palmas, Maria Antonietta

Piras, Maria Grazia

Rauramaa, Rainer

Sanna, Serena

Sassu, Alessandro

Schlessinger, David

Serra, Fabrizio

Sidore, Carlo

Tuomilehto, Jaakko

Uda, Manuela

Usala, Gianluca

Wood, William H.

PLoS Genetics

PubMed

Helsingin yliopiston digitaalinen arkisto

Fine Mapping of Five Loci Associated with Low-Density Lipoprotein Cholesterol Detects Variants That Double the Explained Heritability

Complex trait genome-wide association studies (GWAS) provide an efficient strategy for evaluating large numbers of common variants in large numbers of individuals and for identifying trait-associated variants. Nevertheless, GWAS often leave much of the trait heritability unexplained. We hypothesized that some of this unexplained heritability might be due to common and rare variants that reside in GWAS identified loci but lack appropriate proxies in modern genotyping arrays. To assess this hypothesis, we re-examined 7 genes (APOE, APOC1, APOC2, SORT1, LDLR, APOB, and PCSK9) in 5 loci associated with low-density lipoprotein cholesterol (LDL-C) in multiple GWAS. For each gene, we first catalogued genetic variation by re-sequencing 256 Sardinian individuals with extreme LDL-C values. Next, we genotyped variants identified by us and by the 1000 Genomes Project (totaling 3,277 SNPs) in 5,524 volunteers. We found that in one locus (PCSK9) the GWAS signal could be explained by a previously described low-frequency variant and that in three loci (PCSK9, APOE, and LDLR) there were additional variants independently associated with LDL-C, including a novel and rare LDLR variant that seems specific to Sardinians. Overall, this more detailed assessment of SNP variation in these loci increased estimates of the heritability of LDL-C accounted for by these genes from 3.1% to 6.5%. All association signals and the heritability estimates were successfully confirmed in a sample of ~10,000 Finnish and Norwegian individuals. Our results thus suggest that focusing on variants accessible via GWAS can lead to clear underestimates of the trait heritability explained by a set of loci. Further, our results suggest that, as prelude to large-scale sequencing efforts, targeted re-sequencing efforts paired with large-scale genotyping will increase estimates of complex trait heritability explained by known loci

Sanna, S

Li, BS

Mulas, A

Sidore, C

Kang, HM

Jackson, AU

Piras, MG

Usala, G

Maninchedda, G

Sassu, A

Serra, F

Palmas, MA

Wood, WH

Njølstad, Inger

Laakso, M

Tuomilehto, J

Lakka, TA

Rauramaa, R

Boehnke, M

Cucca, F

Uda, M

Schlessinger, D

Nagaraja, R

Abecasis, GR

Munin - Open Research Archive

English

Wood, William H., III

Julkari

NORA - Norwegian Open Research Archives

Fine Mapping of Five Loci Associated with Low-DensityLipoprotein Cholesterol Detects Variants That Double the Explained Heritability

Complex trait genome-wide association studies (GWAS) provide an efficient strategy for evaluating large numbers of common variants in large numbers of individuals and for identifying trait-associated variants. Nevertheless, GWAS often leave much of the trait heritability unexplained. We hypothesized that some of this unexplained heritability might be due to common and rare variants that reside in GWAS identified loci but lack appropriate proxies in modern genotyping arrays. To assess this hypothesis, we re-examined 7 genes (APOE, APOC1, APOC2, SORT1, LDLR, APOB, and PCSK9) in 5 loci associated with low-density lipoprotein cholesterol (LDL-C) in multiple GWAS. For each gene, we first catalogued genetic variation by re-sequencing 256 Sardinian individuals with extreme LDL-C values. Next, we genotyped variants identified by us and by the 1000 Genomes Project (totaling 3,277 SNPs) in 5,524 volunteers. We found that in one locus (PCSK9) the GWAS signal could be explained by a previously described low-frequency variant and that in three loci (PCSK9, APOE, and LDLR) there were additional variants independently associated with LDL-C, including a novel and rare LDLR variant that seems specific to Sardinians. Overall, this more detailed assessment of SNP variation in these loci increased estimates of the heritability of LDL-C accounted for by these genes from 3.1% to 6.5%. All association signals and the heritability estimates were successfully confirmed in a sample of ∼10,000 Finnish and Norwegian individuals. Our results thus suggest that focusing on variants accessible via GWAS can lead to clear underestimates of the trait heritability explained by a set of loci. Further, our results suggest that, as prelude to large-scale sequencing efforts, targeted re-sequencing efforts paired with large-scale genotyping will increase estimates of complex trait heritability explained by known loci

Serena Sanna

Bingshan Li

Antonella Mulas

Carlo Sidore

Hyun M Kang

Anne U Jackson

Maria Grazia Piras

Gianluca Usala

Giuseppe Maninchedda

Alessandro Sassu

Fabrizio Serra

Maria Antonietta Palmas

William H Wood

Inger Njølstad

Markku Laakso

Kristian Hveem

Jaakko Tuomilehto

Timo A Lakka

Rainer Rauramaa

Michael Boehnke

Francesco Cucca

Manuela Uda

David Schlessinger

Ramaiah Nagaraja

Gonçalo R Abecasis

Directory of Open Access Journals

Fine mapping of five loci associated with low-density lipoprotein cholesterol detects variants that double the explained heritability.

Hyun M. Kang

Anne U. Jackson

William H. Wood

Timo A. Lakka

Gonçalo R. Abecasis

Crossref

A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants.

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Analysis of 12,517 inhabitants of a Sardinian geographic isolate reveals that predispositions to thrombocytopenia and thrombocytosis are inherited traits.

Association of 18 confirmed susceptibility loci for type 2 diabetes with indices of insulin release, proinsulin conversion, and insulin sensitivity in 5,327 nondiabetic Finnish men.

Biological, clinical and population relevance of 95 loci for blood lipids.

Contributions of 18 additional DNA sequence variations in the gene encoding apolipoprotein E to explaining variation in quantitative measures of lipid metabolism.

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Fine-mapping at three loci known to affect fetal hemoglobin levels explains additional genetic variation.

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Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration.

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https://munin.uit.no/bitstream/10037/4016/1/article.pdf

Fine Mapping of Five Loci Associated with Low-Density Lipoprotein Cholesterol Detects Variants That Double the Explained Heritability

Abstract

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Helsingin yliopiston digitaalinen arkisto

Munin - Open Research Archive

Julkari

NORA - Norwegian Open Research Archives

Directory of Open Access Journals

NORA - Norwegian Open Research Archives

Crossref