Genetic Determinants of Telomere Length in African American Youth

ABSTRACTTelomere length (TL) is associated with numerous disease states and is affected by genetic and environmental factors. However, TL has been mostly studied in adult populations of European or Asian ancestry. These studies have identified 34 TL-associated genetic variants recently used as genetic proxies for TL. The generalizability of these associations to pediatric populations and racially diverse populations, specifically of African ancestry, remains unclear. Furthermore, six novel variants associated with TL in a population of European children have been identified but not validated. We measured TL from whole blood samples of 492 healthy African American youth (children and adolescents between 8 and 20 years old) and performed the first genome-wide association study of TL in this population. We were unable to replicate neither the 34 reported genetic associations found in adults nor the six genetic associations found in European children. However, we discovered a novel genome-wide significant association between TL and rs1483898 on chromosome 14. Our results underscore the importance of examining these genetic associations with TL in diverse pediatric populations such as African Americans.

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Molecular genetic aetiology of general cognitive function is enriched in evolutionarily conserved regions

10.1101/063636 ◽

2016 ◽

Cited By ~ 1

Author(s):

W. D. Hill ◽

G. Davies ◽

S. E Harris ◽

S. P. Hagenaars ◽

D. C. Liewald ◽

...

Keyword(s):

Cognitive Function ◽

Genome Wide Association Study ◽

Molecular Genetic ◽

Genetic Correlations ◽

Pleiotropic Effect ◽

Nucleotide Polymorphisms ◽

Genetic Associations ◽

Conserved Regions ◽

Disease States ◽

Genome Wide

AbstractDifferences in general cognitive function have been shown to be partly heritable and to show genetic correlations with a several psychiatric and physical disease states. However, to date few single nucleotide polymorphisms (SNPs) have demonstrated genome-wide significance, hampering efforts aimed at determining which genetic variants are most important for cognitive function and which regions drive the genetic associations between cognitive function and disease states. Here, we combine multiple large genome-wide association study (GWAS) data sets, from the CHARGE cognitive consortium and UK Biobank, to partition the genome into 52 functional annotations and an additional 10 annotations describing tissue-specific histone marks. Using stratified linkage disequilibrium score regression we show that, in two measures of cognitive function, SNPs associated with cognitive function cluster in regions of the genome that are under evolutionary negative selective pressure. These conserved regions contained ~2.6% of the SNPs from each GWAS but accounted for ~ 40% of the SNP-based heritability. The results suggest that the search for causal variants associated with cognitive function, and those variants that exert a pleiotropic effect between cognitive function and health, will be facilitated by examining these enriched regions.

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A Precise Method to Evaluate 360 Degree Measures of Optic Cup and Disc Morphology in an African American Cohort and Its Genetic Applications

Genes ◽

10.3390/genes12121961 ◽

2021 ◽

Vol 12 (12) ◽

pp. 1961

Author(s):

Victoria Addis ◽

Min Chen ◽

Richard Zorger ◽

Rebecca Salowe ◽

Ebenezer Daniel ◽

...

Keyword(s):

African American ◽

Genome Wide Association Study ◽

Area Ratio ◽

Temporal Region ◽

Spearman Correlation ◽

Genetic Associations ◽

Genome Wide ◽

The Mean ◽

Reading Center ◽

Cup To Disc Ratio

(1) Background: Vertical cup-to-disc ratio (CDR) is an important measure for evaluating damage to the optic nerve head (ONH) in glaucoma patients. However, this measure often does not fully capture the irregular cupping observed in glaucomatous nerves. We developed and evaluated a method to measure cup-to-disc ratio (CDR) at all 360 degrees of the ONH. (2) Methods: Non-physician graders from the Scheie Reading Center outlined the cup and disc on digital stereo color disc images from African American patients enrolled in the Primary Open-Angle African American Glaucoma Genetics (POAAGG) study. After converting the resultant coordinates into polar representation, the CDR at each 360-degree location of the ONH was obtained. We compared grader VCDR values with clinical VCDR values, using Spearman correlation analysis, and validated significant genetic associations with clinical VCDR, using grader VCDR values. (3) Results: Graders delineated outlines of the cup contour and disc boundaries twice in each of 1815 stereo disc images. For both cases and controls, the mean CDR was highest at the horizontal bisector, particularly in the temporal region, as compared to other degree locations. There was a good correlation between grader CDR at the vertical bisector and clinical VCDR (Spearman Correlation OD: r = 0.78 [95% CI: 0.76–0.79]). An SNP in the MPDZ gene, associated with clinical VCDR in a prior genome-wide association study, showed a significant association with grader VCDR (p = 0.01) and grader CDR area ratio (p = 0.02). (4) Conclusions: The CDR of both glaucomatous and non-glaucomatous eyes varies by degree location, with the highest measurements in the temporal region of the eye. This method can be useful for capturing innate eccentric ONH morphology, tracking disease progression, and identifying genetic associations.

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86. GENOME-WIDE ASSOCIATION STUDY OF DEPRESSION IN INDIVIDUALS WITH AFRICAN ANCESTRY IDENTIFIES TWO NOVEL GENETIC ASSOCIATIONS

European Neuropsychopharmacology ◽

10.1016/j.euroneuro.2021.07.172 ◽

2021 ◽

Vol 51 ◽

pp. e86-e87

Author(s):

Xiangrui Meng ◽

Yanzhe Feng ◽

Daniel Levey ◽

Olga Giannakopoulou ◽

Arden Moscati ◽

...

Keyword(s):

Association Study ◽

Genome Wide Association Study ◽

African Ancestry ◽

Genome Wide Association ◽

Genetic Associations ◽

Genome Wide

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Eyes of Africa: The Genetics of Blindness: Study Design and Methodology

BMC Ophthalmology ◽

10.1186/s12886-021-02029-8 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Olusola Olawoye ◽

Chimdi Chuka-Okosa ◽

Onoja Akpa ◽

Tony Realini ◽

Michael Hauser ◽

...

Keyword(s):

Genome Wide Association Study ◽

Case Control Study ◽

African Ancestry ◽

Collaborative Study ◽

Data Set ◽

Human Heredity ◽

Genome Wide ◽

A Genome ◽

Multiplex Families ◽

Control Study

Abstract Background This report describes the design and methodology of the “Eyes of Africa: The Genetics of Blindness,” a collaborative study funded through the Human Heredity and Health in Africa (H3Africa) program of the National Institute of Health. Methods This is a case control study that is collecting a large well phenotyped data set among glaucoma patients and controls for a genome wide association study. (GWAS). Multiplex families segregating Mendelian forms of early-onset glaucoma will also be collected for exome sequencing. Discussion A total of 4500 cases/controls have been recruited into the study at the end of the 3rd funded year of the study. All these participants have been appropriately phenotyped and blood samples have been received from these participants. Recent GWAS of POAG in African individuals demonstrated genome-wide significant association with the APBB2 locus which is an association that is unique to individuals of African ancestry. This study will add to the existing knowledge and understanding of POAG in the African population.

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Genome-wide association study of serum metabolites in the African American Study of Kidney Disease and Hypertension

Kidney International ◽

10.1016/j.kint.2021.03.026 ◽

2021 ◽

Author(s):

Shengyuan Luo ◽

Elena V. Feofanova ◽

Adrienne Tin ◽

Sarah Tung ◽

Eugene P. Rhee ◽

...

Keyword(s):

African American ◽

Kidney Disease ◽

Association Study ◽

Genome Wide Association Study ◽

African American Study ◽

Genome Wide Association ◽

American Study ◽

Serum Metabolites ◽

Genome Wide

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A Proteome-Wide Association Study Identified Candidate Human Brain Proteins Associated with Coffee Consumption

10.21203/rs.3.rs-910538/v1 ◽

2021 ◽

Author(s):

Chun'e Li ◽

Xiao Liang ◽

Yumeng Jia ◽

Yan Wen ◽

Huijie Zhang ◽

...

Keyword(s):

Human Brain ◽

Association Study ◽

Plasma Proteins ◽

Genome Wide Association Study ◽

Genetic Correlations ◽

Coffee Consumption ◽

Genetic Associations ◽

Brain Proteins ◽

Genome Wide ◽

Brain Proteome

Abstract Background Increasing evidence suggests the association between caffeine and the brain and nervous system. However, there is limited research on the genetic associations between coffee consumption subtypes and brain proteome, plasma proteomes, and peripheral metabolites. Methods First, proteome-wide association study (PWAS) of coffee consumption subtypes was performed by integrating two independent genome-wide association study (GWAS) datasets (91,462–502,650 subjects) with two reference human brain proteomes (ROS/MAP and Banner), by using the FUSION pipeline. Second, transcriptome-wide association study (TWAS) analysis of coffee consumption subtypes was conducted by integrating the two gene expression weight references (RNAseq and splicing) of brain RNA-seq and the two GWAS datasets (91,462–502,650 subjects) of coffee consumption subtypes. Finally, we used the LD Score Regression (LDSC) analysis to evaluate the genetic correlations of coffee consumption subtypes with plasma proteomes and peripheral metabolites. Results For the traits related to coffee consumption, we identified 3 common PWAS proteins, such as MADD (P PWAS−Banner−dis=0.0114, P PWAS−ROS/MAP−rep =0.0489). In addition, 11 common TWAS genes were found in two cohorts, such as ARPC2 (P TWAS−splicing−dis =2063×10− 12, P TWAS−splicing−dis =1.25×10− 10, P TWAS−splicing−dis =1.24e-08, P TWAS−splicing−rep =3.25×10− 9 and P TWAS−splicing−rep =3.42×10− 13). Importantly, we have identified 8 common genes between PWAS and TWAS, such as ALDH2 (P PWAS−banner−rep =1.22×10− 22, PTWAS− splicing−dis = 4.54×10− 92). For the LDSC analysis of human plasma proteome, we identified 11 plasma proteins, such as CHL1 (P dis = 0.0151, P rep =0.0438). For the LDSC analysis of blood metabolites, 5 metabolites have been found, such as myo-inositol (P dis = 0.0073, P dis = 0.0152, P dis =0.0414, P rep =0.0216). Conclusions We identified several brain proteins and genes associated with coffee consumption subtypes. In addition, we also detected several candidate plasma proteins and metabolites related to these subtypes.

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Kleine-Levin syndrome is associated with birth difficulties and genetic variants in the TRANK1 gene loci

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2005753118 ◽

2021 ◽

Vol 118 (12) ◽

pp. e2005753118

Author(s):

Aditya Ambati ◽

Ryan Hillary ◽

Smaranda Leu-Semenescu ◽

Hanna M. Ollila ◽

Ling Lin ◽

...

Keyword(s):

Bipolar Disorder ◽

Genome Wide Association Study ◽

Perinatal Outcomes ◽

Case Control ◽

Risk Scores ◽

Circadian Regulation ◽

Genetic Associations ◽

Imaging Studies ◽

Genome Wide

Kleine-Levin syndrome (KLS) is a rare disorder characterized by severe episodic hypersomnia, with cognitive impairment accompanied by apathy or disinhibition. Pathophysiology is unknown, although imaging studies indicate decreased activity in hypothalamic/thalamic areas during episodes. Familial occurrence is increased, and risk is associated with reports of a difficult birth. We conducted a worldwide case−control genome-wide association study in 673 KLS cases collected over 14 y, and ethnically matched 15,341 control individuals. We found a strong genome-wide significant association (rs71947865, Odds Ratio [OR] = 1.48, P = 8.6 × 10−9) within the 3′region of TRANK1 gene locus, previously associated with bipolar disorder and schizophrenia. Strikingly, KLS cases with rs71947865 variant had significantly increased reports of a difficult birth. As perinatal outcomes have dramatically improved over the last 40 y, we further stratified our sample by birth years and found that recent cases had a significantly reduced rs71947865 association. While the rs71947865 association did not replicate in the entire follow-up sample of 171 KLS cases, rs71947865 was significantly associated with KLS in the subset follow-up sample of 59 KLS cases who reported birth difficulties (OR = 1.54, P = 0.01). Genetic liability of KLS as explained by polygenic risk scores was increased (pseudo R2 = 0.15; P < 2.0 × 10−22 at P = 0.5 threshold) in the follow-up sample. Pathway analysis of genetic associations identified enrichment of circadian regulation pathway genes in KLS cases. Our results suggest links between KLS, circadian regulation, and bipolar disorder, and indicate that the TRANK1 polymorphisms in conjunction with reported birth difficulties may predispose to KLS.

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Alcohol consumption and telomere length: observational and Mendelian randomization approaches

10.1101/2021.09.17.21263720 ◽

2021 ◽

Author(s):

Anya Topiwala ◽

Bernd Taschler ◽

Klaus P Ebmeier ◽

Steve Smith ◽

Hang Zhou ◽

...

Keyword(s):

Alcohol Consumption ◽

Telomere Length ◽

Alcohol Use Disorder ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Prevention Strategies ◽

Genome Wide ◽

Non Linear ◽

Alcoholic Drinks ◽

Potential Threshold

Alcohols impact on telomere length, a proposed marker of biological age, is unclear. We performed the largest observational study to date and compared findings with Mendelian randomization (MR) estimates. Two-sample MR used data from a recent genome-wide association study (GWAS) of telomere length. Genetic variants were selected on the basis of associations with alcohol consumption and alcohol use disorder (AUD). Non-linear MR employed UK Biobank individual data. MR analyses suggest a causal relationship between alcohol and telomere length: both genetically predicted alcohol traits were inversely associated with telomere length. 1 S.D. higher genetically-predicted log-transformed alcoholic drinks weekly had a -0.07 S.D. effect on telomere length (95% confidence interval [CI]:-0.14 to -0.01); genetically-predicted AUD -0.06 S.D. effect (CI:-0.10 to -0.02). Results were consistent across methods and independent from smoking. Non-linear analyses indicated a potential threshold relationship between alcohol and telomere length. Our findings have implications for potential aging-related disease prevention strategies.

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