Genome-wide association study of phenotypes measuring progression from first cocaine or opioid use to dependence reveals novel risk genes

Aim: Substance use disorders (SUD) result in substantial morbidity and mortality worldwide. Opioids, and to a lesser extent cocaine, contribute to a large percentage of this health burden. Despite their high heritability, few genetic risk loci have been identified for either opioid or cocaine dependence (OD or CD, respectively). A genome-wide association study of OD and CD related phenotypes reflecting the time between first self-reported use of these substances and a first DSM-IV dependence diagnosis was conducted. Methods: Cox proportional hazards regression in a discovery sample of 6,188 African-Americans (AAs) and 6,835 European-Americans (EAs) participants in a genetic study of multiple substance dependence phenotypes were used to test for association between genetic variants and these outcomes. The top findings were tested for replication in two independent cohorts. Results: In the discovery sample, three independent regions containing variants associated with time to dependence at P < 5 × 10−8 were identified, one (rs61835088 = 1.03 × 10−8) for cocaine in the combined EA-AA meta-analysis in the gene FAM78B on chromosome 1, and two for opioids in the AA portion of the sample in intergenic regions of chromosomes 4 (rs4860439, P = 1.37 × 10−8) and 9 (rs7032521, P = 3.30 × 10−8). After meta-analysis with data from the replication cohorts, the signal at rs61835088 improved (HR = 0.87, P = 3.71 × 10−9 and an intergenic SNP on chromosome 21 (rs2825295, HR = 1.14, P = 2.57 × 10−8) that missed the significance threshold in the AA discovery sample became genome-wide significant (GWS) for CD. Conclusions: Although the two GWS variants are not in genes with obvious links to SUD biology and have modest effect sizes, they are statistically robust and show evidence for association in independent samples. These results may point to novel pathways contributing to disease progression and highlight the utility of related phenotypes to better understand the genetics of SUDs.

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Genome-wide association study of phenotypes measuring progression from first cocaine or opioid use to dependence reveals novel risk genes

Exploration of Medicine ◽

10.37349/emed.2020.00032 ◽

2021 ◽

Author(s):

Richard Sherva ◽

Congcong Zhu ◽

Leah Wetherill ◽

Howard J. Edenberg ◽

Emma Johnson ◽

...

Keyword(s):

Association Study ◽

Genome Wide Association Study ◽

Meta Analysis ◽

Chromosome 21 ◽

Genome Wide Association ◽

Chromosome 1 ◽

Opioid Use ◽

Discovery Sample ◽

Genome Wide ◽

A Genome

Aim: Substance use disorders (SUD) result in substantial morbidity and mortality worldwide. Opioids, and to a lesser extent cocaine, contribute to a large percentage of this health burden. Despite their high heritability, few genetic risk loci have been identified for either opioid or cocaine dependence (OD or CD, respectively). A genome-wide association study of OD and CD related phenotypes reflecting the time between first self-reported use of these substances and a first DSM-IV dependence diagnosis was conducted. Methods: Cox proportional hazards regression in a discovery sample of 6,188 African-Americans (AAs) and 6,835 European-Americans (EAs) participants in a genetic study of multiple substance dependence phenotypes were used to test for association between genetic variants and these outcomes. The top findings were tested for replication in two independent cohorts. Results: In the discovery sample, three independent regions containing variants associated with time to dependence at P < 5 x 10-8 were identified, one (rs61835088 = 1.03 x 10-8) for cocaine in the combined EA-AA meta-analysis in the gene FAM78B on chromosome 1, and two for opioids in the AA portion of the sample in intergenic regions of chromosomes 4 (rs4860439, P = 1.37 x 10-8) and 9 (rs7032521, P = 3.30 x 10-8). After meta-analysis with data from the replication cohorts, the signal at rs61835088 improved (HR = 0.87, P = 3.71 x 10-9 and an intergenic SNP on chromosome 21 (rs2825295, HR = 1.14, P = 2.57 x 10-8) that missed the significance threshold in the AA discovery sample became genome-wide significant (GWS) for CD. Conclusions: Although the two GWS variants are not in genes with obvious links to SUD biology and have modest effect sizes, they are statistically robust and show evidence for association in independent samples. These results may point to novel pathways contributing to disease progression and highlight the utility of related phenotypes to better understand the genetics of SUDs.

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Faculty Opinions recommendation of Risk loci for chronic obstructive pulmonary disease: a genome-wide association study and meta-analysis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718310292.793531798 ◽

2017 ◽

Author(s):

Erik Melen

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Association Study ◽

Pulmonary Disease ◽

Genome Wide Association Study ◽

Meta Analysis ◽

Genome Wide Association ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Genome Wide ◽

A Genome

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Genetic variations and risk of placental abruption: A genome-wide association study and meta-analysis of genome-wide association studies

Placenta ◽

10.1016/j.placenta.2018.04.008 ◽

2018 ◽

Vol 66 ◽

pp. 8-16 ◽

Cited By ~ 2

Author(s):

Tsegaselassie Workalemahu ◽

Daniel A. Enquobahrie ◽

Bizu Gelaye ◽

Sixto E. Sanchez ◽

Pedro J. Garcia ◽

...

Keyword(s):

Association Study ◽

Genome Wide Association Study ◽

Placental Abruption ◽

Association Studies ◽

Meta Analysis ◽

Genetic Variations ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Genome Wide ◽

A Genome

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A genome-wide association study meta-analysis of clinical fracture in 10,012 African American women

Bone Reports ◽

10.1016/j.bonr.2016.08.005 ◽

2016 ◽

Vol 5 ◽

pp. 233-242 ◽

Cited By ~ 8

Author(s):

Kira C. Taylor ◽

Daniel S. Evans ◽

Digna R. Velez Edwards ◽

Todd L. Edwards ◽

Tamar Sofer ◽

...

Keyword(s):

African American ◽

Association Study ◽

African American Women ◽

Genome Wide Association Study ◽

Meta Analysis ◽

Genome Wide Association ◽

American Women ◽

Clinical Fracture ◽

Genome Wide ◽

A Genome

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Genome-wide association study reveals 14 new SNPs and confirms two structural variants highly associated with the horned/polled phenotype in goats

BMC Genomics ◽

10.1186/s12864-021-08089-w ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Jiazhong Guo ◽

Rui Jiang ◽

Ayi Mao ◽

George E. Liu ◽

Siyuan Zhan ◽

...

Keyword(s):

Association Study ◽

Mixed Model ◽

Genome Wide Association Study ◽

Insertion Site ◽

Genome Wide Association ◽

Chromosome 1 ◽

Structural Variants ◽

Diagnostic Pcr ◽

Genome Wide ◽

A Genome

Abstract Background There is a long-term interest in investigating the genetic basis of the horned/polled phenotype in domestic goats. Here, we report a genome-wide association study (GWAS) to detect the genetic loci affecting the polled phenotype in goats. Results We obtained a total of 13,980,209 biallelic SNPs, using the genotyping-by-sequencing data from 45 Jintang Black (JT) goats, which included 32 female and nine male goats, and four individuals with the polled intersex syndrome (PIS). Using a mixed-model based GWAS, we identified two association signals, which were located at 150,334,857–150,817,260 bp (P = 5.15 × 10− 119) and 128,286,704–131,306,537 bp (P = 2.74 × 10− 15) on chromosome 1. The genotype distributions of the 14 most significantly associated SNPs were completely correlated with horn status in goats, based on the whole-genome sequencing (WGS) data from JT and two other Chinese horned breeds. However, variant annotation suggested that none of the detected SNPs within the associated regions were plausible causal mutations. Via additional read-depth analyses and visual inspections of WGS data, we found a 10.1-kb deletion (CHI1:g. 129424781_129434939del) and a 480-kb duplication (CHI1:150,334,286–150,818,098 bp) encompassing two genes KCNJ15 and ERG in the associated regions of polled and PIS-affected goats. Notably, the 10.1-kb deletion also served as the insertion site for the 480-kb duplication, as validated by PCR and Sanger sequencing. Our WGS genotyping showed that all horned goats were homozygous for the reference alleles without either the structural variants (SVs), whereas the PIS-affected goats were homozygous for both the SVs. We also demonstrated that horned, polled, and PIS-affected individuals among 333 goats from JT and three other Chinese horned breeds can be accurately classified via PCR amplification and agarose gel electrophoresis of two fragments in both SVs. Conclusion Our results revealed that two genomic regions on chromosome 1 are major loci affecting the polled phenotypes in goats. We provided a diagnostic PCR to accurately classify horned, polled, and PIS-affected goats, which will enable a reliable genetic test for the early-in-life prediction of horn status in goats.

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A genome-wide association study of treatment-resistant depression and meta-analysis with STAR*D

10.26226/morressier.5b681762b56e9b005965c121 ◽

2018 ◽

Author(s):

Chiara Fabbri

Keyword(s):

Association Study ◽

Genome Wide Association Study ◽

Meta Analysis ◽

Genome Wide Association ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

Genome Wide ◽

A Genome ◽

Resistant Depression

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The International SSRI Pharmacogenomics Consortium (ISPC): a genome-wide association study of antidepressant treatment response

Translational Psychiatry ◽

10.1038/tp.2015.47 ◽

2015 ◽

Vol 5 (4) ◽

pp. e553-e553 ◽

Cited By ~ 75

Author(s):

J M Biernacka ◽

K Sangkuhl ◽

G Jenkins ◽

R M Whaley ◽

P Barman ◽

...

Keyword(s):

Association Study ◽

Selective Serotonin Reuptake Inhibitors ◽

Genome Wide Association Study ◽

Transmembrane Domain ◽

Meta Analysis ◽

Genome Wide Association ◽

Research Network ◽

Genome Wide ◽

A Genome ◽

Increased Risk

Abstract Response to treatment with selective serotonin reuptake inhibitors (SSRIs) varies considerably between patients. The International SSRI Pharmacogenomics Consortium (ISPC) was formed with the primary goal of identifying genetic variation that may contribute to response to SSRI treatment of major depressive disorder. A genome-wide association study of 4-week treatment outcomes, measured using the 17-item Hamilton Rating Scale for Depression (HRSD-17), was performed using data from 865 subjects from seven sites. The primary outcomes were percent change in HRSD-17 score and response, defined as at least 50% reduction in HRSD-17. Data from two prior studies, the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomics Study (PGRN-AMPS) and the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, were used for replication, and a meta-analysis of the three studies was performed (N=2394). Although many top association signals in the ISPC analysis map to interesting candidate genes, none were significant at the genome-wide level and the associations were not replicated using PGRN-AMPS and STAR*D data. Top association results in the meta-analysis of response included single-nucleotide polymorphisms (SNPs) in the HPRTP4 (hypoxanthine phosphoribosyltransferase pseudogene 4)/VSTM5 (V-set and transmembrane domain containing 5) region, which approached genome-wide significance (P=5.03E−08) and SNPs 5’ upstream of the neuregulin-1 gene, NRG1 (P=1.20E−06). NRG1 is involved in many aspects of brain development, including neuronal maturation and variations in this gene have been shown to be associated with increased risk for mental disorders, particularly schizophrenia. Replication and functional studies of these findings are warranted.

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Genome-wide association study of early-onset bipolar I disorder in the Han Taiwanese population

Translational Psychiatry ◽

10.1038/s41398-021-01407-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Lawrence Shih-Hsin Wu ◽

Ming-Chyi Huang ◽

Cathy Shen-Jang Fann ◽

Hsien-Yuan Lane ◽

Chian-Jue Kuo ◽

...

Keyword(s):

Bipolar Disorder ◽

Association Study ◽

Early Onset ◽

Genome Wide Association Study ◽

Genetic Locus ◽

Meta Analysis ◽

Genome Wide Association ◽

Genome Wide ◽

A Genome ◽

Chinese Descent

AbstractThe search for susceptibility genes underlying the heterogeneous bipolar disorder has been inconclusive, often with irreproducible results. There is a hope that narrowing the phenotypes will increase the power of genetic analysis. Early-onset bipolar disorder is thought to be a genetically homogeneous subtype with greater symptom severity. We conducted a genome-wide association study (GWAS) for this subtype in bipolar I (BPI) disorder. Study participants included 1779 patients of Han Chinese descent with BPI disorder recruited by the Taiwan Bipolar Consortium. We conducted phenotype assessment using the Chinese version of the Schedules for Clinical Assessment in Neuropsychiatry and prepared a life chart with graphic depiction of lifetime clinical course for each of the BPI patient recruited. The assessment of onset age was based on this life chart with early onset defined as ≤20 years of age. We performed GWAS in a discovery group of 516 early-onset and 790 non-early-onset BPI patients, followed by a replication study in an independent group of 153 early-onset and 320 non-early-onset BPI patients and a meta-analysis with these two groups. The SNP rs11127876, located in the intron of CADM2, showed association with early-onset BPI in the discovery cohort (P = 7.04 × 10−8) and in the test of replication (P = 0.0354). After meta-analysis, this SNP was demonstrated to be a new genetic locus in CADM2 gene associated with early-onset BPI disorder (P = 5.19 × 10−8).

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Integration of genome-wide association study and expression quantitative trait locus mapping for identification of endometriosis-associated genes

Scientific Reports ◽

10.1038/s41598-020-79515-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Ya-Ching Chou ◽

Ming-Jer Chen ◽

Pi-Hua Chen ◽

Ching-Wen Chang ◽

Mu-Hsien Yu ◽

...

Keyword(s):

Association Study ◽

Quantitative Trait ◽

Genome Wide Association Study ◽

Chromosome 9 ◽

Genome Wide Association ◽

Chromosome 1 ◽

Eqtl Analysis ◽

Taiwanese Population ◽

Genome Wide ◽

A Genome

AbstractTo determine whether genetic predisposition to endometriosis varies depending on ethnicity and in association with expression quantitative trait loci (eQTL) in a Taiwanese population. We conducted a genome-wide association study (GWAS) and replicated it in 259 individuals with laparoscopy-confirmed stage III or IV endometriosis (cases) and 171 women without endometriosis (controls). Their genomic DNA was extracted from blood and evaluated by the GWAS of Taiwan Biobank Array. Novel genetic variants that predispose individuals to endometriosis were identified using GWAS and replication, including rs10739199 (P = 6.75 × 10−5) and rs2025392 (P = 8.01 × 10−5) at chromosome 9, rs1998998 (P = 6.5 × 10−6) at chromosome 14, and rs6576560 (P = 9.7 × 10−6) at chromosome 15. After imputation, strong signals were exhibited by rs10822312 (P = 1.80 × 10−7) at chromosome 10, rs58991632 (P = 1.92 × 10−6) and rs2273422 (P = 2.42 × 10−6) at chromosome 20, and rs12566078 (P = 2.5 × 10−6) at chromosome 1. We used the Genotype-Tissue Expression (GTEx) database to observe eQTL. Among these SNPs, the cis-eQTL rs13126673 of inturned planar cell polarity protein (INTU) showed significant association with INTU expression (P = 5.1 × 10–33). Moreover, the eQTL analysis was performed on endometriotic tissues from women with endometriosis. The expression of INTU in 78 endometriotic tissue of women with endometriosis is associated with rs13126673 genotype (P = 0.034). To our knowledge, this is the first GWAS to link endometriosis and eQTL in a Taiwanese population.

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