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Rare variants in the splicing regulatory elements of EXOC3L4 are associated with brain glucose metabolism in Alzheimer's disease.

ABSTRACT: BACKGROUND:Alzheimer's disease (AD) is one of the most common neurodegenerative diseases that causes problems related to brain function. To some extent it is understood on a molecular level how AD arises, however there are a lack of biomarkers that can be used for early diagnosis. Two popular methods to identify AD-related biomarkers use genetics and neuroimaging. Genes and neuroimaging phenotypes have provided some insights as to the potential for AD biomarkers. While the field of imaging-genomics has identified genetic features associated with structural and functional neuroimaging phenotypes, it remains unclear how variants that affect splicing could be important for understanding the genetic etiology of AD. METHODS:In this study, rare variants (minor allele frequency?

SUBMITTER: Miller JE

PROVIDER: S-EPMC6156983 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Rare variants in the splicing regulatory elements of EXOC3L4 are associated with brain glucose metabolism in Alzheimer's disease.

Miller Jason E JE Shivakumar Manu K MK Lee Younghee Y Han Seonggyun S Horgousluoglu Emrin E Risacher Shannon L SL Saykin Andrew J AJ Nho Kwangsik K Kim Dokyoon D

BMC medical genomics 20180914 Suppl 3

<h4>Background</h4>Alzheimer's disease (AD) is one of the most common neurodegenerative diseases that causes problems related to brain function. To some extent it is understood on a molecular level how AD arises, however there are a lack of biomarkers that can be used for early diagnosis. Two popular methods to identify AD-related biomarkers use genetics and neuroimaging. Genes and neuroimaging phenotypes have provided some insights as to the potential for AD biomarkers. While the field of imagi ...[more]

PMID: 30255815

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Project description:The invention of high throughput sequencing technologies has led to the discoveries of hundreds of thousands of genetic variants associated with thousands of human diseases. Many of these genetic variants are located outside the protein coding regions, and as such, it is challenging to interpret the function of these genetic variants by traditional genetic approaches. Recent genome-wide functional genomics studies, such as FANTOM5 and ENCODE have uncovered a large number of regulatory elements across hundreds of different tissues or cell lines in the human genome. These findings provide an opportunity to study the interaction between regulatory elements and disease-associated genetic variants. Identifying these diseased-related regulatory elements will shed light on understanding the mechanisms of how these variants regulate gene expression and ultimately result in disease formation and progression.In this study, we curated and categorized 27,558 Mendelian disease variants, 20,964 complex disease variants, 5,809 cancer predisposing germline variants, and 43,364 recurrent cancer somatic mutations. Compared against nine different types of regulatory regions from FANTOM5 and ENCODE projects, we found that different types of disease variants show distinctive propensity for particular regulatory elements. Mendelian disease variants and recurrent cancer somatic mutations are 22-fold and 10- fold significantly enriched in promoter regions respectively (q<0.001), compared with allele-frequency-matched genomic background. Separate from these two categories, cancer predisposing germline variants are 27-fold enriched in histone modification regions (q<0.001), 10-fold enriched in chromatin physical interaction regions (q<0.001), and 6-fold enriched in transcription promoters (q<0.001). Furthermore, Mendelian disease variants and recurrent cancer somatic mutations share very similar distribution across types of functional effects. We further found that regulatory regions are located within over 50% coding exon regions. Transcription promoters, methylation regions, and transcription insulators have the highest density of disease variants, with 472, 239, and 72 disease variants per one million base pairs, respectively.Disease-associated variants in different disease categories are preferentially located in particular regulatory elements. These results will be useful for an overall understanding about the differences among the pathogenic mechanisms of various disease-associated variants.

Dataset Information

Rare variants in the splicing regulatory elements of EXOC3L4 are associated with brain glucose metabolism in Alzheimer's disease.

Publications

Rare variants in the splicing regulatory elements of EXOC3L4 are associated with brain glucose metabolism in Alzheimer's disease.

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