Meta-Analysis of Genome-Wide Scans for Total Body BMD in Children and Adults Reveals Allelic Heterogeneity and Age-Specific Effects at the WNT16 Locus

AbstractCataract is the leading cause of blindness among the elderly worldwide and cataract surgery is one of the most common operations performed in the United States. As the genetic etiology of cataract formation remains unclear, we conducted a multiethnic genome-wide association meta-analysis, combining results from the GERA and UK Biobank cohorts, and tested for replication in the 23andMe research cohort. We report 54 genome-wide significant loci, 37 of which were novel. Sex-stratified analyses identified CASP7 as an additional novel locus specific to women. We show that genes within or near 80% of the cataract-associated loci are significantly expressed and/or enriched-expressed in the mouse lens across various spatiotemporal stages as per iSyTE analysis. Furthermore, iSyTE shows 32 candidate genes in the associated loci have altered gene expression in 9 different gene perturbation mouse models of lens defects/cataract, suggesting their relevance to lens biology. Our work provides further insight into the complex genetic architecture of cataract susceptibility.

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Identification of four novel associations for B-cell acute lymphoblastic leukaemia risk

Nature Communications ◽

10.1038/s41467-019-13069-6 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 12

Author(s):

Jayaram Vijayakrishnan ◽

Maoxiang Qian ◽

James B. Studd ◽

Wenjian Yang ◽

Ben Kinnersley ◽

...

Keyword(s):

Acute Lymphoblastic Leukaemia ◽

B Cell ◽

Lymphoblastic Leukaemia ◽

Association Studies ◽

Meta Analysis ◽

Chromatin Interaction ◽

Genome Wide Association Studies ◽

Specific Effects ◽

Risk Variants ◽

Genome Wide

AbstractThere is increasing evidence for a strong inherited genetic basis of susceptibility to acute lymphoblastic leukaemia (ALL) in children. To identify new risk variants for B-cell ALL (B-ALL) we conducted a meta-analysis with four GWAS (genome-wide association studies), totalling 5321 cases and 16,666 controls of European descent. We herein describe novel risk loci for B-ALL at 9q21.31 (rs76925697, P = 2.11 × 10−8), for high-hyperdiploid ALL at 5q31.1 (rs886285, P = 1.56 × 10−8) and 6p21.31 (rs210143 in BAK1, P = 2.21 × 10−8), and ETV6-RUNX1 ALL at 17q21.32 (rs10853104 in IGF2BP1, P = 1.82 × 10−8). Particularly notable are the pleiotropic effects of the BAK1 variant on multiple haematological malignancies and specific effects of IGF2BP1 on ETV6-RUNX1 ALL evidenced by both germline and somatic genomic analyses. Integration of GWAS signals with transcriptomic/epigenomic profiling and 3D chromatin interaction data for these leukaemia risk loci suggests deregulation of B-cell development and the cell cycle as central mechanisms governing genetic susceptibility to ALL.

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A multiethnic GWAS meta-analysis of 585,243 individuals identifies new risk loci associated with cataract and reveals sex-specific effects

10.1101/2020.09.23.20200428 ◽

2020 ◽

Author(s):

Helene Choquet ◽

Ronald B. Melles ◽

Deepti Anand ◽

Jie Yin ◽

Gabriel Cuellar-Partida ◽

...

Keyword(s):

Meta Analysis ◽

The Elderly ◽

Effect Sizes ◽

Uk Biobank ◽

Altered Gene Expression ◽

Specific Effects ◽

Genome Wide ◽

Altered Gene ◽

Mouse Lens ◽

Gene Perturbation

Cataract is the leading cause of blindness among the elderly worldwide and cataract surgery is one of the most common operations performed in the United States1-3. The etiology remains largely unclear, and to contribute to its elucidation we conducted a multiethnic genome-wide association meta-analysis of cataract, combining results from the GERA and UK Biobank cohorts, and tested for replication in the research cohort from 23andMe, Inc.. We report 54 genome-wide significant loci, 37 of which were previously unknown. Sex-stratified analyses identified two additional novel loci (CASP7 and GSTM2) specific to women and sex differences in effect sizes and significance of association at five other loci. We show that genes within or near 80% of the cataract-associated loci are significantly expressed and/or enriched-expressed in the mouse lens across various spatiotemporal stages. Further, 32 candidate genes in the associated loci have altered gene expression in 9 different gene perturbation mouse models of lens defects/cataract, suggesting their relevance to lens biology.

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