Screening Low-Frequency SNPS From Genome-Wide Association Study Reveals a New Risk Allele for Progression to AIDS

Abstract Background Acute lymphoblastic leukemia (ALL) is the most common cancer in children and can arise in B or T lymphoid lineages. Although risk loci have been identified for B-ALL, the inherited basis of T-ALL is mostly unknown, with a particular paucity of genome-wide investigation of susceptibility variants in large patient cohorts. Methods We performed a genome-wide association study (GWAS) in 1191 children with T-ALL and 12 178 controls, with independent replication using 117 cases and 5518 controls. The associations were tested using an additive logistic regression model. Top risk variants were tested for effects on enhancer activity using luciferase assay. All statistical tests were two sided. Results A novel risk locus in the USP7 gene (rs74010351, odds ratio [OR] = 1.44, 95% confidence interval [CI] = 1.27 to 1.65, P = 4.51 × 10–8) reached genome-wide significance in the discovery cohort, with independent validation (OR = 1.51, 95% CI = 1.03 to 2.22, P = .04). The USP7 risk allele was overrepresented in individuals of African descent, thus contributing to the higher incidence of T-ALL in this race/ethnic group. Genetic changes in USP7 (germline variants or somatic mutations) were observed in 56.4% of T-ALL with TAL1 overexpression, statistically significantly higher than in any other subtypes. Functional analyses suggested this T-ALL risk allele is located in a putative cis-regulatory DNA element with negative effects on USP7 transcription. Finally, comprehensive comparison of 14 susceptibility loci in T- vs B-ALL pointed to distinctive etiology of these leukemias. Conclusions These findings indicate strong associations between inherited genetic variation and T-ALL susceptibility in children and shed new light on the molecular etiology of ALL, particularly commonalities and differences in the biology of the two major subtypes (B- vs T-ALL).

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Genome-Wide Association Study of lipid traits in youth with type 2 diabetes

Journal of the Endocrine Society ◽

10.1210/jendso/bvab139 ◽

2021 ◽

Author(s):

Nicola Santoro ◽

Ling Chen ◽

Jennifer Todd ◽

Jasmin Divers ◽

Amy S Shah ◽

...

Keyword(s):

Type 2 Diabetes ◽

Association Study ◽

Genome Wide Association Study ◽

Risk Allele ◽

Density Lipoprotein ◽

Genome Wide Association ◽

Relationship Matrix ◽

Genome Wide ◽

A Genome

Abstract Context Dyslipidemia is highly prevalent in youth with type 2 diabetes (T2D), yet the pathogenic components of dyslipidemia in youth with T2D are poorly understood. Objective To evaluate the genetic determinants of lipid traits in youth with T2D through a genome-wide association study (GWAS). Design, participants and main outcome measures We genotyped 206,928 variants and imputed 17,642,824 variants in 1,076 youth (mean age 15.0 ±2.48 years) with T2D from the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) and SEARCH for Diabetes in Youth (SEARCH) studies as part of the Progress in Diabetes Genetics in Youth (ProDiGY) consortium. We performed association testing for triglyceride, low-density lipoprotein (LDL-c) and high-density lipoprotein (HDL-c) concentrations adjusted for the genetic relationship matrix within each sub-study followed by meta-analyses for each trait. Results We identified a novel association between a deletion on chromosome 3 (3:67817380_AT/A_Deletion:RP11-81N13.1) and triglyceride levels at genome-wide level of significance (P=2.3×10 -8) with each risk allele increasing triglycerides by 20%. We also identified a genome-wide significant signal at rs247617 (P=5.1×10 -9) between HERFUD1 and CETP associated with HDL-c, with carriers of one copy of the risk allele having twice higher HDL-c. Conclusions Our genetic analyses of lipid traits in youth with T2D have identified one novel and one previously known locus. Additional studies are needed to further characterize the genetic architecture of dyslipidemia in youth with T2D.

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Genome-wide association study of Hirschsprung disease detects a novel low-frequency variant at the RET locus

European Journal of Human Genetics ◽

10.1038/s41431-017-0053-7 ◽

2018 ◽

Vol 26 (4) ◽

pp. 561-569 ◽

Cited By ~ 10

Author(s):

João Fadista ◽

Marie Lund ◽

Line Skotte ◽

Frank Geller ◽

Priyanka Nandakumar ◽

...

Keyword(s):

Association Study ◽

Genome Wide Association Study ◽

Low Frequency ◽

Hirschsprung Disease ◽

Genome Wide Association ◽

Genome Wide

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Genome-wide association study identifies common and low-frequency variants at theAMHgene locus that strongly predict serum AMH levels in males

Human Molecular Genetics ◽

10.1093/hmg/ddv465 ◽

2015 ◽

Vol 25 (2) ◽

pp. 382-388 ◽

Cited By ~ 9

Author(s):

John R.B. Perry ◽

George McMahon ◽

Felix R. Day ◽

Susan M Ring ◽

Scott M. Nelson ◽

...

Keyword(s):

Association Study ◽

Genome Wide Association Study ◽

Low Frequency ◽

Genome Wide Association ◽

Genome Wide

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Systematic detection of Mendelian and non-Mendelian variants associated with retinitis pigmentosa by genome-wide association study

10.1101/859744 ◽

2019 ◽

Author(s):

Koji M Nishiguchi ◽

Fuyuki Miya ◽

Yuka Mori ◽

Kosuke Fujita ◽

Masato Akiyama ◽

...

Keyword(s):

Retinitis Pigmentosa ◽

Association Study ◽

Genome Wide Association Study ◽

Genetic Diagnosis ◽

Low Frequency ◽

Japanese Patients ◽

Genome Wide Association ◽

Genome Wide ◽

Synonymous Variant ◽

First Time

AbstractTo uncover genetic basis of autosomal recessive retinitis pigmentosa (ARRP), we applied 2-step genome-wide association study (GWAS) in 640 Japanese patients prescreened with targeted re-sequencing. Meta-GWAS identified three independent peaks at P < 5.0×10-8, all within the major ARRP gene EYS. Two were each tagged by a low frequency variant (allele frequency < 0.05); a known founder Mendelian mutation (c.4957dupA, p.S1653Kfs*2) and a presumably hypomorphic non-synonymous variant (c.2528G>A, p.G843E). c.2528G>A newly solved 7.0% of Japanese ARRP cases, improving genetic diagnosis by 26.8% and simultaneously serving as a new attractive target for genome editing gene therapy. The third peak was tagged by an intronic common variant, representing a novel disease-susceptibility signal. GWAS successfully unraveled genetic causes of a rare “monogenic” disorder for the first time, which provided unexpected insights into significant contribution of non-Mendelian genetic factors and identified a novel high frequency variant directly linked to development of local genome therapeutics.

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Genome-wide association study identifies novel susceptibility loci for migraine in Han Chinese resided in Taiwan

Cephalalgia ◽

10.1177/0333102417695105 ◽

2017 ◽

Vol 38 (3) ◽

pp. 466-475 ◽

Cited By ~ 8

Author(s):

Shih-Pin Chen ◽

Jong-Ling Fuh ◽

Ming-Yi Chung ◽

Ying-Chao Lin ◽

Yi-Chu Liao ◽

...

Keyword(s):

Association Study ◽

Genome Wide Association Study ◽

Risk Allele ◽

Positive Association ◽

Susceptibility Genes ◽

Han Chinese ◽

Genome Wide Association ◽

Nucleotide Polymorphisms ◽

Significance Level ◽

Genome Wide

Background Susceptibility genes for migraine, despite it being a highly prevalent and disabling neurological disorder, have not been analyzed in Asians by genome-wide association study (GWAS). Methods We conducted a two-stage case-control GWAS to identify susceptibility genes for migraine without aura in Han Chinese residing in Taiwan. In the discovery stage, we genotyped 1005 clinic-based Taiwanese migraine patients and 1053 population-based sex-matched controls using Axiom Genome-Wide CHB Array. In the replication stage, we genotyped 27 single-nucleotide polymorphisms with p < 10−4 in 1120 clinic-based migraine patients and 604 sex-matched normal controls by using Sequenom. Variants at LRP1, TRPM8, and PRDM, which have been replicated in Caucasians, were also genotyped. Results We identified a novel susceptibility locus (rs655484 in DLG2) that reached GWAS significance level for migraine risk in Han Chinese ( p = 1.45 × 10−12, odds ratio [OR] = 2.42), and also another locus (rs3781545in GFRA1) with suggestive significance ( p = 1.27 × 10−7, OR = 1.38). In addition, we observed positive association signals with a similar trend to the associations identified in Caucasian GWASs for rs10166942 in TRPM8 (OR = 1.33, 95% confidence interval [CI] = 1.14–1.54, Ppermutation = 9.99 × 10−5; risk allele: T) and rs1172113 in LRP1 (OR = 1.23, 95% CI = 1.04–1.45, Ppermutation = 2.9 × 10−2; risk allele: T). Conclusion The present study is the first migraine GWAS conducted in Han-Chinese and Asians. The newly identified susceptibility genes have potential implications in migraine pathogenesis. DLG2 is involved in glutamatergic neurotransmission, and GFRA1 encodes GDNF receptors that are abundant in CGRP-containing trigeminal neurons. Furthermore, positive association signals for TRPM8 and LRP1 suggest the possibility for common genetic contributions across ethnicities.

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A hypomorphic variant in EYS detected by genome-wide association study contributes toward retinitis pigmentosa

Communications Biology ◽

10.1038/s42003-021-01662-9 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Koji M. Nishiguchi ◽

Fuyuki Miya ◽

Yuka Mori ◽

Kosuke Fujita ◽

Masato Akiyama ◽

...

Keyword(s):

Linkage Disequilibrium ◽

Retinitis Pigmentosa ◽

Association Study ◽

Genome Wide Association Study ◽

Low Frequency ◽

Japanese Patients ◽

Genome Wide Association ◽

Genome Wide ◽

Unknown Significance ◽

Synonymous Variant

AbstractThe genetic basis of Japanese autosomal recessive retinitis pigmentosa (ARRP) remains largely unknown. Herein, we applied a 2-step genome-wide association study (GWAS) in 640 Japanese patients. Meta-GWAS identified three independent peaks at P < 5.0 × 10−8, all within the major ARRP gene EYS. Two of the three were each in linkage disequilibrium with a different low frequency variant (allele frequency < 0.05); a known founder Mendelian mutation (c.4957dupA, p.S1653Kfs*2) and a non-synonymous variant (c.2528 G > A, p.G843E) of unknown significance. mRNA harboring c.2528 G > A failed to restore rhodopsin mislocalization induced by morpholino-mediated knockdown of eys in zebrafish, consistent with the variant being pathogenic. c.2528 G > A solved an additional 7.0% of Japanese ARRP cases. The third peak was in linkage disequilibrium with a common non-synonymous variant (c.7666 A > T, p.S2556C), possibly representing an unreported disease-susceptibility signal. GWAS successfully unraveled genetic causes of a rare monogenic disorder and identified a high frequency variant potentially linked to development of local genome therapeutics.

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