scholarly journals Biological insights from multi-omic analysis of 31 genomic risk loci for adult hearing difficulty

2019 ◽  
Author(s):  
Gurmannat Kalra ◽  
Beatrice Milon ◽  
Alex M. Casella ◽  
Yang Song ◽  
Brian R. Herb ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Meta Analysis ◽  
Significant Risk ◽  
Sensory Epithelium ◽  
Open Chromatin ◽  
Specific Expression ◽  
Risk Genes ◽  
Age Related ◽  
Genome Wide ◽  
Hearing Difficulty

ABSTRACTAge-related hearing impairment (ARHI), one of the most common medical conditions, is strongly heritable, yet its genetic causes remain largely unknown. We conducted a meta-analysis of GWAS summary statistics from multiple hearing-related traits in the UK Biobank (n = up to 323,978) and identified 31 genome-wide significant risk loci for self-reported hearing difficulty (p < 5e-8), of which 30 have not been reported previously in the peer-reviewed literature at genome-wide significance. We investigated the regulatory and cell specific expression for these loci by generating mRNA-seq, ATAC-seq, and single-cell RNA-seq from cells in the mouse cochlea. Risk-associated genes were most strongly enriched for expression in cochlear epithelial cells, as well as for genes related to sensory perception and known Mendelian deafness genes, supporting their relevance to auditory function. Regions of the human genome homologous to open chromatin in sensory epithelial cells from the mouse were strongly enriched for heritable risk for hearing difficulty, even after adjusting for baseline effects of evolutionary conservation and cell-type nonspecific regulatory regions. Epigenomic and statistical fine-mapping most strongly supported 50 putative risk genes. Of these, at least 39 were expressed robustly in mouse cochlea and 16 were enriched specifically in sensory hair cells. These results reveal new risk loci and risk genes for hearing difficulty and suggest an important role for altered gene regulation in the cochlear sensory epithelium.

scholarly journals Replication of CD58 and CLEC16A as genome-wide significant risk genes for multiple sclerosis

2009 ◽  
Vol 54 (11) ◽  
pp. 676-680 ◽  
Author(s):  
Ilse A Hoppenbrouwers ◽  
Yurii S Aulchenko ◽  
A Cecile Janssens ◽  
Sreeram V Ramagopalan ◽  
Linda Broer ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Significant Risk ◽  
Risk Genes ◽  
Genome Wide

scholarly journals A genome-wide analysis of open chromatin in human tracheal epithelial cells reveals novel candidate regulatory elements for lung function

Thorax ◽  
2011 ◽  
Vol 67 (5) ◽  
pp. 385-391 ◽  
Author(s):  
Jared M Bischof ◽  
Christopher J Ott ◽  
Shih-Hsing Leir ◽  
Nehal Gosalia ◽  
Lingyun Song ◽  
...  
Keyword(s):  
Lung Function ◽  
Epithelial Cells ◽  
Regulatory Elements ◽  
Open Chromatin ◽  
Genome Wide Analysis ◽  
Tracheal Epithelial Cells ◽  
Genome Wide ◽  
A Genome ◽  
Tracheal Epithelial

scholarly journals A regulatory variant of CHRM3 is associated with cannabis-induced hallucinations in European Americans

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Zhongshan Cheng ◽  
Chureerat Phokaew ◽  
Yi-Ling Chou ◽  
Dongbing Lai ◽  
Jacquelyn L. Meyers ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Collaborative Study ◽  
Risk Genes ◽  
European Americans ◽  
Genome Wide ◽  
Nominal Significance ◽  
A Genome ◽  
Regulatory Variant

AbstractCannabis, the most widely used illicit drug, can induce hallucinations. Our understanding of the biology of cannabis-induced hallucinations (Ca-HL) is limited. We used the Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA) to identify cannabis-induced hallucinations (Ca-HL) among long-term cannabis users (used cannabis ≥1 year and ≥100 times). A genome-wide association study (GWAS) was conducted by analyzing European Americans (EAs) and African Americans (AAs) in Yale-Penn 1 and 2 cohorts individually, then meta-analyzing the two cohorts within population. In the meta-analysis of Yale-Penn EAs (n = 1917), one genome-wide significant (GWS) signal emerged at the CHRM3 locus, represented by rs115455482 (P = 1.66 × 10−10), rs74722579 (P = 2.81 × 10−9), and rs1938228 (P = 1.57 × 10−8); signals were GWS in Yale-Penn 1 EAs (n = 1092) and nominally significant in Yale-Penn 2 EAs (n = 825). Two SNPs, rs115455482 and rs74722579, were available from the Collaborative Study on the Genetics of Alcoholism data (COGA; 3630 long-term cannabis users). The signals did not replicate, but when meta-analyzing Yale-Penn and COGA EAs, the two SNPs’ association signals were increased (meta-P-values 1.32 × 10−10 and 2.60 × 10−9, respectively; n = 4291). There were no significant findings in AAs, but in the AA meta-analysis (n = 3624), nominal significance was seen for rs74722579. The rs115455482*T risk allele was associated with lower CHRM3 expression in the thalamus. CHRM3 was co-expressed with three psychosis risk genes (GABAG2, CHRNA4, and HRH3) in the thalamus and other human brain tissues and mouse GABAergic neurons. This work provides strong evidence for the association of CHRM3 with Ca-HL and provides insight into the potential involvement of thalamus for this trait.

scholarly journals Subcellular distribution of adenosine deaminase and adenosine deaminase-complexing protein in rabbit kidney: implications for adenosine metabolism.

1994 ◽  
Vol 42 (6) ◽  
pp. 775-782 ◽  
Author(s):  
W P Schrader ◽  
C A West ◽  
U H Rudofsky ◽  
W A Samsonoff
Keyword(s):  
Epithelial Cells ◽  
Adenosine Deaminase ◽  
Brush Border ◽  
Renal Tissue ◽  
Proximal Tubules ◽  
Rabbit Kidney ◽  
Specific Cell ◽  
Specific Expression ◽  
Age Related ◽  
S3 Segment

We evaluated the age-related distribution of adenosine deaminase (ADA) and adenosine deaminase-complexing protein (CP) in rabbit kidney by immunohistochemical staining procedures. Paraffin- or resin-embedded tissue from rabbits < 1 week-4 years of age were stained by the peroxidase-anti-peroxidase (PAP) method for ADA and CP. With the exception of neonates, the qualitative staining pattern of each protein remained generally constant with age. In the cortex, distal tubules, blood vessels, histiocytes, and epithelial cells lining Bowman's capsule stained for ADA. Proximal tubules and glomeruli were positive for CP. In contrast to the segregated pattern in the cortex, staining for ADA and CP overlapped in the corticomedullary junction. ADA and CP co-localized on the brush border of tubule cells of the S3 segment. In the cytoplasm of these cells, staining for ADA was characterized by scattered punctuate deposits of peroxidase reaction product. In some instances these punctuate deposits also appeared to be positive for CP. In medulla, epithelial cells of the thin limb were positive for both ADA and CP, whereas papillary collecting ducts stained only for CP. These results document the age-related, tissue-specific expression and localization of ADA in renal tissue, features that probably reflect the crucial role played by the enzyme in adenosine/deoxyadenosine catabolism. In addition, colocalization of ADA and CP on the brush border of cells in the S3 segment of proximal tubules provides support for the hypothesis that one function of CP may be to position ADA on the plasma membrane of specific cell populations, further expanding the enzyme's utility in nucleoside metabolism.

scholarly journals Common variants in SOX-2 and congenital cataract genes contribute to age-related nuclear cataract

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Ekaterina Yonova-Doing ◽  
Wanting Zhao ◽  
Robert P. Igo ◽  
Chaolong Wang ◽  
Periasamy Sundaresan ◽  
...  
Keyword(s):  
Congenital Cataract ◽  
Association Studies ◽  
Meta Analysis ◽  
Crystalline Lens ◽  
Genome Wide Association Studies ◽  
Nuclear Cataract ◽  
Common Variants ◽  
Age Related ◽  
Genome Wide ◽  
Common Genetic Variants

AbstractNuclear cataract is the most common type of age-related cataract and a leading cause of blindness worldwide. Age-related nuclear cataract is heritable (h2 = 0.48), but little is known about specific genetic factors underlying this condition. Here we report findings from the largest to date multi-ethnic meta-analysis of genome-wide association studies (discovery cohort N = 14,151 and replication N = 5299) of the International Cataract Genetics Consortium. We confirmed the known genetic association of CRYAA (rs7278468, P = 2.8 × 10−16) with nuclear cataract and identified five new loci associated with this disease: SOX2-OT (rs9842371, P = 1.7 × 10−19), TMPRSS5 (rs4936279, P = 2.5 × 10−10), LINC01412 (rs16823886, P = 1.3 × 10−9), GLTSCR1 (rs1005911, P = 9.8 × 10−9), and COMMD1 (rs62149908, P = 1.2 × 10−8). The results suggest a strong link of age-related nuclear cataract with congenital cataract and eye development genes, and the importance of common genetic variants in maintaining crystalline lens integrity in the aging eye.

scholarly journals Trans-ethnic meta-analysis identifies new loci associated with longitudinal blood pressure traits

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mateus H. Gouveia ◽  
Amy R. Bentley ◽  
Hampton Leonard ◽  
Karlijn A. C. Meeks ◽  
Kenneth Ekoru ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Association Studies ◽  
Meta Analysis ◽  
Regulatory Function ◽  
Genome Wide Association Studies ◽  
The Novel ◽  
Cross Sectional ◽  
Age Related ◽  
Genome Wide ◽  
The Us

AbstractGenome-wide association studies (GWAS) have identified thousands of genetic loci associated with cross-sectional blood pressure (BP) traits; however, GWAS based on longitudinal BP have been underexplored. We performed ethnic-specific and trans-ethnic GWAS meta-analysis using longitudinal and cross-sectional BP data of 33,720 individuals from five cohorts in the US and one in Brazil. In addition to identifying several known loci, we identified thirteen novel loci with nine based on longitudinal and four on cross-sectional BP traits. Most of the novel loci were ethnic- or study-specific, with the majority identified in African Americans (AA). Four of these discoveries showed additional evidence of association in independent datasets, including an intergenic variant (rs4060030, p = 7.3 × 10–9) with reported regulatory function. We observed a high correlation between the meta-analysis results for baseline and longitudinal average BP (rho = 0.48). BP trajectory results were more correlated with those of average BP (rho = 0.35) than baseline BP(rho = 0.18). Heritability estimates trended higher for longitudinal traits than for cross-sectional traits, providing evidence for different genetic architectures. Furthermore, the longitudinal data identified up to 20% more BP known associations than did cross-sectional data. Our analyses of longitudinal BP data in diverse ethnic groups identified novel BP loci associated with BP trajectory, indicating a need for further longitudinal GWAS on BP and other age-related traits.

scholarly journals The genetic architecture of age-related hearing impairment revealed by genome-wide association analysis

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Erna V. Ivarsdottir ◽  
Hilma Holm ◽  
Stefania Benonisdottir ◽  
Thorhildur Olafsdottir ◽  
Gardar Sveinbjornsson ◽  
...  
Keyword(s):  
Hearing Impairment ◽  
Genetic Architecture ◽  
Rare Variants ◽  
Meta Analysis ◽  
Genetic Risk Score ◽  
Missense Variant ◽  
Genome Wide Association ◽  
Age Related ◽  
Genome Wide ◽  
A Genome

AbstractAge-related hearing impairment (ARHI) is the most common sensory disorder in older adults. We conducted a genome-wide association meta-analysis of 121,934 ARHI cases and 591,699 controls from Iceland and the UK. We identified 21 novel sequence variants, of which 13 are rare, under either additive or recessive models. Of special interest are a missense variant in LOXHD1 (MAF = 1.96%) and a tandem duplication in FBF1 covering 4 exons (MAF = 0.22%) associating with ARHI (OR = 3.7 for homozygotes, P = 1.7 × 10−22 and OR = 4.2 for heterozygotes, P = 5.7 × 10−27, respectively). We constructed an ARHI genetic risk score (GRS) using common variants and showed that a common variant GRS can identify individuals at risk comparable to carriers of rare high penetrance variants. Furthermore, we found that ARHI and tinnitus share genetic causes. This study sheds a new light on the genetic architecture of ARHI, through several rare variants in both Mendelian deafness genes and genes not previously linked to hearing.

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