Abundant Quantitative Trait Loci Exist for DNA Methylation and Gene Expression in Human Brain

Gibbs, J. Raphael; Brug, Marcel P. van der; Hernandez, Dena G.; Traynor, Bryan J.; Nalls, Michael A.; Lai, Shiao Lin; Arepalli, Sampath; Dillman, Allissa; Rafferty, Ian; Troncoso, Juan C.; Johnson, Robert; Zielke, H. Ronald; Ferrucci, Luigi; Longo, Dan L.; Cookson, Mark; Singleton, Andrew B.

doi:10.1371/journal.pgen.1000952

Cited by 738 publications

(869 citation statements)

References 31 publications

Supporting

Mentioning

792

Contrasting

Unclassified

Order By: Relevance

“…Residuals from the regression analysis for each probe were then used as the quantitative trait for that probe in genome-wide association analysis looking for eQTLs, performed using the assoc function within PLINK, which correlates allele dosage with change in the trait (17,18).…”

Section: Methodsmentioning

confidence: 99%

Kinesin-associated protein 3 (KIFAP3) has no effect on survival in a population-based cohort of ALS patients

Traynor¹,

Nalls

Lai

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

It was recently reported that rs1541160 on chromosome 1q24.2 has a marked effect on survival of amyotrophic lateral sclerosis (ALS) patients by influencing KIFAP3 expression. The cohorts used in that study were collected from ALS specialty clinics. We attempted to replicate these findings in a population-based cohort of 504 Italian ALS patients. None of 140 SNPs genotyped within the KIFAP3 locus (including rs1541160) had an effect on survival (log-rank P value for rs1541160 = 0.47) or on gene expression in that region. These data illustrate the complexities associated with analyzing ALS phenotypes for association. A myotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by rapidly progressive paralysis leading to death from respiratory failure. Population-based epidemiological studies indicate that the median survival of ALS patients is 20-36 mo (1-3). Demographic and clinical features, as well as riluzole and certain symptomatic therapies, are known to modestly modify survival, but the influence of genetics on the rate of disease progression and survival is not known (4). Landers et al. (5) recently reported that the CC genotype of SNP rs1541160 within the kinesin-associated protein 3 (KIFAP3) gene on chromosome 1q24.2 conferred a 14-mo survival advantage on ALS patients. Furthermore, expression data based on 26 occipital lobe brain samples suggested that the CC genotype of this SNP reduced KIFAP3 expression by 41% compared with the TT genotype (5). To confirm the accuracy of this report, we attempted to replicate this finding in a population-based cohort of 504 Italian ALS patients collected using the Piemonte and Valle d'Aosta Registry for ALS (PARALS). We also evaluated the effect of the identified SNP, and all SNPs within the 1-Mb surrounding region, on the expression of KIFAP3 in four brain regions obtained from 144 neurologically normal individuals. ResultsRs1541160 had no effect on survival in our population-based cohort of 504 Italian ALS cases either under the genotypic model [median survival for CC genotype = 4.09 y; CT genotype = 3.48 y; TT genotype = 3.58 y; log-rank P = 0.48, Peto P = 0.60 (Fig. 1A)] or under the allelic model [log-rank P = 0.33, Peto P = 0.53 (Fig. 1B)]. Similarly, survival analysis limited to the 318 deceased ALS patients failed to demonstrate an effect of rs1541160 on survival either under the genotypic model [log-rank P = 0.55, Peto P = 0.92 (Fig. 1C)] or under the allelic model [log-rank P = 0.42, Peto P = 0.71 (Fig. 1D)]. Linear regression modeling of the deceasedonly cohort, incorporating age, gender, site of symptom onset, and population structure (component vectors 1 and 2 from multidimensional scaling) as covariates, was also not significant (β coefficient = 0.024, P = 0.89). Survival analysis limited to the cohort of patients attending a specialized ALS clinic was similarly negative [n = 89 patients (Fig. S1)]. None of the 139 other SNPs within the 1-Mb region surrounding KIFAP3 significantly influenced survival of the Italian ALS cohort (...

show abstract

Section: Methodsmentioning

confidence: 99%

Kinesin-associated protein 3 (KIFAP3) has no effect on survival in a population-based cohort of ALS patients

Traynor¹,

Nalls

Lai

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

show abstract

“…1). As cis ‐effects on gene expression can be specific to developmental stage [Hill and Bray, 2012; Tao et al, 2014] and brain region [Buonocore et al, 2010; Gibbs et al, 2010; Ramasamy et al, 2014], we examined effects in the human fetal brain as well as in three adult brain regions implicated in the pathophysiology of schizophrenia: dorsolateral prefrontal cortex (DLPFC), hippocampus, and caudate.…”

Section: Introductionmentioning

confidence: 99%

Genome‐wide significant schizophrenia risk variation on chromosome 10q24 is associated with altered cis‐regulation of BORCS7, AS3MT, and NT5C2 in the human brain

Duarte

Troakes

Nolan

et al. 2016

American J of Med Genetics Pt B

View full text Add to dashboard Cite

Chromosome 10q24.32‐q24.33 is one of the most robustly supported risk loci to emerge from genome‐wide association studies (GWAS) of schizophrenia. However, extensive linkage disequilibrium makes it difficult to distinguish the actual susceptibility gene(s) at the locus, limiting its value for improving biological understanding of the condition. In the absence of coding changes that can account for the association, risk is likely conferred by altered regulation of one or more genes in the region. We, therefore, used highly sensitive measures of allele‐specific expression to assess cis‐regulatory effects associated with the two best‐supported schizophrenia risk variants (SNP rs11191419 and indel ch10_104957618_I/rs202213518) on the primary positional candidates BORCS7, AS3MT, CNNM2, and NT5C2 in the human brain. Heterozygosity at rs11191419 was associated with increased allelic expression of BORCS7 and AS3MT in the fetal and adult brain, and with reduced allelic expression of NT5C2 in the adult brain. Heterozygosity at ch10_104957618_I was associated with reduced allelic expression of NT5C2 in both the fetal and adult brain. Comparisons between cDNA ratios in heterozygotes and homozygotes for the risk alleles indicated that cis‐effects on NT5C2 expression in the adult dorsolateral prefrontal cortex could be largely accounted for by genotype at these two risk variants. While not excluding effects on other genes in the region, this study implicates altered neural expression of BORCS7, AS3MT, and NT5C2 in susceptibility to schizophrenia arising from genetic variation at the chromosome 10q24 locus. © 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.

show abstract

“…13 Several genome-wide association studies with methylation quantitative trait loci (mQTL) in both cis and trans locations have confirmed the genetic heritability of DNA methylation. 14,17,18 However, it is difficult to understand to what extent the observed familial resemblance in DNA methylation is due to genetic heritability and/or common environmental effect.…”

Section: Introductionmentioning

confidence: 99%

Familial resemblances in blood leukocyte DNA methylation levels

et al. 2016

View full text Add to dashboard Cite

show abstract

Abundant Quantitative Trait Loci Exist for DNA Methylation and Gene Expression in Human Brain

Cited by 738 publications

References 31 publications

Kinesin-associated protein 3 (KIFAP3) has no effect on survival in a population-based cohort of ALS patients

Kinesin-associated protein 3 (KIFAP3) has no effect on survival in a population-based cohort of ALS patients

Genome‐wide significant schizophrenia risk variation on chromosome 10q24 is associated with altered cis‐regulation of BORCS7, AS3MT, and NT5C2 in the human brain

Familial resemblances in blood leukocyte DNA methylation levels

Contact Info

Product

Resources

About