Low-density lipoprotein receptor mutations generate synthetic genome-wide associations

Oosterveer, Daniëlla M.; Versmissen, Jorie; Defesche, Joep C.; Sivapalaratnam, Suthesh; Yazdanpanah, Mojgan; Mulder, Monique; Zee, Leonie van der; Uitterlinden, André G.; Duijn, Cornelia M. van; Hofman, Albert; Kastelein, John J.P.; Aulchenko, Yurii S.; Sijbrands, Eric J.G.

doi:10.1038/ejhg.2012.207

Cited by 7 publications

(7 citation statements)

References 16 publications

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“…D′ = 0.95 and 0.96, respectively, with rs4905179) and generally with many common variants in this locus (Figure 4), suggesting little genetic recombination. This proof-of-principle approach, revealing that signals of common variants in fact merely reflect rarer variants, has recently also been shown for some of the loci regulating low-density lipoprotein (LDL) cholesterol [31], [32]. Yet for other loci linked to LDL cholesterol, as well as for loci influencing other traits, both common and low-frequent variants contributed independently of the original GWAS signal to the phenotypic trait [31], [33], [34].…”

Section: Discussionmentioning

confidence: 89%

Causal and Synthetic Associations of Variants in the SERPINA Gene Cluster with Alpha1-antitrypsin Serum Levels

et al. 2013

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Several infrequent genetic polymorphisms in the SERPINA1 gene are known to substantially reduce concentration of alpha1-antitrypsin (AAT) in the blood. Since low AAT serum levels fail to protect pulmonary tissue from enzymatic degradation, these polymorphisms also increase the risk for early onset chronic obstructive pulmonary disease (COPD). The role of more common SERPINA1 single nucleotide polymorphisms (SNPs) in respiratory health remains poorly understood.We present here an agnostic investigation of genetic determinants of circulating AAT levels in a general population sample by performing a genome-wide association study (GWAS) in 1392 individuals of the SAPALDIA cohort.Five common SNPs, defined by showing minor allele frequencies (MAFs) >5%, reached genome-wide significance, all located in the SERPINA gene cluster at 14q32.13. The top-ranking genotyped SNP rs4905179 was associated with an estimated effect of β = −0.068 g/L per minor allele (P = 1.20*10−12). But denser SERPINA1 locus genotyping in 5569 participants with subsequent stepwise conditional analysis, as well as exon-sequencing in a subsample (N = 410), suggested that AAT serum level is causally determined at this locus by rare (MAF<1%) and low-frequent (MAF 1–5%) variants only, in particular by the well-documented protein inhibitor S and Z (PI S, PI Z) variants. Replication of the association of rs4905179 with AAT serum levels in the Copenhagen City Heart Study (N = 8273) was successful (P<0.0001), as was the replication of its synthetic nature (the effect disappeared after adjusting for PI S and Z, P = 0.57). Extending the analysis to lung function revealed a more complex situation. Only in individuals with severely compromised pulmonary health (N = 397), associations of common SNPs at this locus with lung function were driven by rarer PI S or Z variants. Overall, our meta-analysis of lung function in ever-smokers does not support a functional role of common SNPs in the SERPINA gene cluster in the general population.

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Section: Discussionmentioning

confidence: 89%

Causal and Synthetic Associations of Variants in the SERPINA Gene Cluster with Alpha1-antitrypsin Serum Levels

et al. 2013

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“…Empirical studies, involving resequencing of GWAS loci, have now found several instances where GWAS signals for various disorders or traits can be partially or largely attributed to effects of rare variants at the associated locus (Oosterveer et al, 2013;Sanna et al, 2011;Saunders et al, 2014;Thun et al, 2013). This effect has not been seen in all cases, however (Hunt et al, 2013).…”

Section: Common Variants -Genome--wide Association Studiesmentioning

confidence: 99%

The genetic architecture of neurodevelopmental disorders

Mitchell¹

2014

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Neurodevelopmental disorders include rare conditions caused by identified single mutations, such as Fragile X, Down and Angelman syndromes, and much more common clinical categories such as autism, epilepsy and schizophrenia.These common conditions are all highly heritable but their genetics is considered to be "complex". In fact, this sharp dichotomy in genetic architecture between rare and common disorders may be largely artificial. On the one hand, much of the apparent complexity in the genetics of common disorders may derive from underlying genetic heterogeneity, which has remained obscure until recently. On the other hand, even for supposedly Mendelian conditions, the relationship between single mutations and clinical phenotypes is rarely simple.The categories of monogenic and complex disorders may therefore merge across a continuum, with some mutations being strongly associated with specific syndromes and others having a more variable outcome, modified by the presence of additional genetic variants.

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“…Several common variant association studies (CVASs) formerly called genome‐wide association studies (GWASs), resequencing and targeted approaches have revealed a wealth of information on the genetic basis for dyslipidemia, and several predisposing genes identified thus far have been implicated in hypercholesterolemia , hypertriglyceridemia or low HDL‐cholesterol levels . Despite the volume of these data on dyslipidemia‐related genes, only a fraction of the heritability of the disease traits has been explained thus far, and the predisposing gene variants, particularly for LHDLC, are far from being completely unraveled .…”

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confidence: 99%

A common variant association study reveals novel susceptibility loci for low HDL‐cholesterol levels in ethnic Arabs

et al. 2016

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The genetic susceptibility to acquiring low high density lipoprotein-cholesterol (LHDLC) levels is not completely elucidated yet. In this study, we performed a common variant association study for harboring this trait in ethnic Arabs. We employed the Affymetrix high-density Axiom Genome-Wide ASI Array (Asian population) providing a coverage of 598,000 single nucleotide variations (SNPs) to genotype 5495 individuals in a two-phase study involving discovery and validation sets of experiments. The rs1800775 [1.31 (1.22-1.42); p = 3.41E-12] in the CETP gene and rs359027 [1.26 (1.16-1.36); p = 2.55E-08] in the LMCD1 gene were significantly associated with LHDLC levels. Furthermore, rs3104435 [1.26 (1.15-1.38); p = 1.19E-06] at the MATN1 locus, rs9835344 [1.16 (1.08-1.26); p = 8.75E-06] in the CNTN6 gene, rs1559997 [1.3 (1.14-1.47); p = 9.48E-06] in the SDS gene and rs1670273 [1.2 (1.1-1.31); p = 4.81E-06] in the DMN/SYNM gene exhibited suggestive association with the disorder. Seven other variants including rs1147169 in the PLCL1 gene, rs10248618 in the DNAH11, rs476155 in the GLIS3, rs7024300 in the ABCA1, intergenic rs10836699, rs11603691 in P2RX3 and rs750134 in CORO1C gene exhibited borderline protective properties. Validation and joint meta-analysis resulted in rs1800775, rs3104435 and rs359027 retaining their predisposing properties, while rs10836699 and rs11603691 showed protective properties. Our data show several predisposing variants across the genome for LHDLC levels in ethnic Arabs.

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Low-density lipoprotein receptor mutations generate synthetic genome-wide associations

Cited by 7 publications

References 16 publications

Causal and Synthetic Associations of Variants in the SERPINA Gene Cluster with Alpha1-antitrypsin Serum Levels

Causal and Synthetic Associations of Variants in the SERPINA Gene Cluster with Alpha1-antitrypsin Serum Levels

The genetic architecture of neurodevelopmental disorders

A common variant association study reveals novel susceptibility loci for low HDL‐cholesterol levels in ethnic Arabs

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