Comprehensive promoter level expression quantitative trait loci analysis of the human frontal lobe.
Expression quantitative trait loci (eQTL) analysis is a powerful method to detect correlations between gene expression and genomic variants and is widely used to interpret the biological mechanism underlying identified genome wide association studies (GWAS) risk loci. Numerous eQTL studies have been performed on different cell types and tissues of which the majority has been based on microarray technology.



We present here an eQTL analysis based on cap analysis gene expression sequencing (CAGEseq) data created from human postmortem frontal lobe tissue combined with genotypes obtained through genotyping arrays, exome sequencing, and CAGEseq. Using CAGEseq as an expression profiling technique combined with these different genotyping techniques allows measurement of the molecular effect of variants on individual transcription start sites and increases the resolution of eQTL analysis by also including the non-annotated parts of the genome.



We identified 2410 eQTLs and show that non-coding transcripts are more likely to contain an eQTL than coding transcripts, in particular antisense transcripts. We provide evidence for how previously identified GWAS loci for schizophrenia (NRGN), Parkinson's disease, and Alzheimer's disease (PARK16 and MAPT loci) could increase the risk for disease at a molecular level. Furthermore, we demonstrate that CAGEseq improves eQTL analysis because variants obtained from CAGEseq are highly enriched for having a functional effect and thus are an efficient method towards the identification of causal variants.



Our data contain both coding and non-coding transcripts and has the added value that we have identified eQTLs for variants directly adjacent to TSS. Future eQTL studies would benefit from combining CAGEseq with RNA sequencing for a more complete interpretation of the transcriptome and increased understanding of eQTL signals.
Applied Genomics for Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany. cornelis.blauwendraat@gmail.com.
Cornelis
C
Blauwendraat
Genome Biology of Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
Margherita
M
Francescatto
Laboratory of Neurogenetics, National Institute on Aging (NIA), Bethesda, Maryland, USA.|Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK.
J Raphael
JR
Gibbs
Genome Biology of Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.|Department of Clinical Genetics, VU University Medical Center (VUmc), Amsterdam, The Netherlands.
Iris E
IE
Jansen
Genome Biology of Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.|Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
Javier
J
Simón-Sánchez
Laboratory of Neurogenetics, National Institute on Aging (NIA), Bethesda, Maryland, USA.
Dena G
DG
Hernandez
Laboratory of Neurogenetics, National Institute on Aging (NIA), Bethesda, Maryland, USA.
Allissa A
AA
Dillman
Laboratory of Neurogenetics, National Institute on Aging (NIA), Bethesda, Maryland, USA.
Andrew B
AB
Singleton
Laboratory of Neurogenetics, National Institute on Aging (NIA), Bethesda, Maryland, USA.
Mark R
MR
Cookson
Applied Genomics for Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
Patrizia
P
Rizzu
Genome Biology of Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.|Department of Clinical Genetics, VU University Medical Center (VUmc), Amsterdam, The Netherlands.|Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
Peter
P
Heutink
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D030541:Databases, Genetic; D005260:Female; D005625:Frontal Lobe / Q000737:chemistry*; D015870:Gene Expression; D014644:Genetic Variation; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D040641:Quantitative Trait Loci; D055815:Young Adult
Cap analysis gene expression sequencing (CAGEseq); Expression quantitative trait loci (eQTL); NRGN; PARK16; frontal lobe cortex