Epiretinal membrane (ERM) is a common retinal condition characterized by the presence of fibrocellular tissue on the retinal surface, often with visual distortion and loss of visual acuity. We ...studied European American (EUR), African American (AFR), and Latino (admixed American, AMR) ERM participants in the Million Veteran Program (MVP) for genome-wide association analysis—a total of 38,232 case individuals and 557,988 control individuals. We completed a genome-wide association study (GWAS) in each population separately, and then results were meta-analyzed. Genome-wide significant (GWS) associations were observed in all three populations studied: 31 risk loci in EUR subjects, 3 in AFR, and 2 in AMR, with 48 in trans-ancestry meta-analysis. Many results replicated in the FinnGen sample. Several GWS variants associate to alterations in gene expression in the macula. ERM showed significant genetic correlation to multiple traits. Pathway enrichment analyses implicated collagen and collagen-adjacent mechanisms, among others. This well-powered ERM GWAS identified novel genetic associations that point to biological mechanisms for ERM.
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•Epiretinal membrane (macular pucker) often causes visual impairment•This genome-wide association study identifies genetic risk variants in three populations•The identified variants implicate both known and novel biology•Results may lead to new treatments and personalized risk prediction
Epiretinal membrane (ERM) is a common retinal condition that often causes visual distortion and loss of visual acuity. For symptomatic ERM, vitrectomy with epiretinal membrane peeling is the typical treatment. We completed GWAS in European American, African American, and Latino ERM participants in the VA Million Veteran Program (MVP) and identified significant associations in each population. ERM showed significant genetic correlation to multiple traits. This well-powered ERM GWAS identified novel genetic associations that point to biological mechanisms.
Approximately 697,000 members of the U.S. Armed Forces were deployed to the Persian Gulf in support of the 1990-1991 Persian Gulf War (GW). Subsequently, many deployed and some non-deployed veterans ...developed a chronic multi-symptom illness, now named Gulf War Illness (GWI). This manuscript outlines the methods and rationale for studying the genomics of GWI within the Million Veteran Program (MVP), a VA-based national research program that has linked medical records, surveys, and genomic data, enabling genome-wide association studies (GWASs).
MVP participants who served in the military during the GW era were contacted by mail and invited to participate in the GWI study. A structured health questionnaire, based on a previously tested instrument, was also included in the mailing. Data on deployment locations and exposures, symptoms associated with GWI, clinical diagnoses, personal habits, and health care utilization were collected. Self-reported data will be augmented with chart reviews and structured international classification of disease codes, to classify participants by GWI case status. We will develop a phenotyping algorithm, based on two commonly used case definitions, to determine GWI status, and then conduct a nested case-control GWAS. Genetic variants associated with GWI will be investigated, and gene-gene and gene-environment interactions studied. The genetic overlap of GWI with, and causative mechanisms linking this illness to, other health conditions and the effects of genomic regulatory mechanisms on GWI risk will also be explored.
The proposed initial GWAS described in this report will investigate the genomic underpinnings of GWI with a large sample size and state-of-the-art genomic analyses and phenotyping. The data generated will provide a rich and expansive foundation on which to build additional analyses.
Decades of research have shown that environmental exposures, including self-reports of trauma, are partly heritable. Heritable characteristics may influence exposure to and interpretations of ...environmental factors. Identifying heritable factors associated with self-reported trauma could improve our understanding of vulnerability to exposure and the interpretation of life events.
We used genome-wide association study summary statistics of childhood maltreatment, defined as reporting of abuse (emotional, sexual, and physical) and neglect (emotional and physical) (N = 185,414 participants). We calculated genetic correlations (rg) between reported childhood maltreatment and 576 traits to identify phenotypes that might explain the heritability of reported childhood maltreatment, retaining those with |rg| > 0.25. We specified multiple regression models using genomic structural equation modeling to detect residual genetic variance in childhood maltreatment after accounting for genetically correlated traits.
In 2 separate models, the shared genetic component of 12 health and behavioral traits and 7 psychiatric disorders accounted for 59% and 56% of heritability due to common genetic variants (single nucleotide polymorphism–based heritability h2SNP) of childhood maltreatment, respectively. Genetic influences on h2SNP of childhood maltreatment were generally accounted for by a shared genetic component across traits. The exceptions to this were general risk tolerance, subjective well-being, posttraumatic stress disorder, and autism spectrum disorder, identified as independent contributors to h2SNP of childhood maltreatment. These 4 traits alone were sufficient to explain 58% of h2SNP of childhood maltreatment.
We identified putative traits that reflect h2SNP of childhood maltreatment. Elucidating the mechanisms underlying these associations may improve trauma prevention and posttraumatic intervention strategies.
Alcohol genome-wide association studies (GWASs) have generally focused on alcohol consumption and alcohol use disorder (AUD); few have examined habitual drinking behaviors like maximum habitual ...alcohol intake (MaxAlc).
To identify genetic loci associated with MaxAlc and to elucidate the genetic architecture across alcohol traits.
This MaxAlc genetic association study was performed among Million Veteran Program participants enrolled from January 10, 2011, to September 30, 2020. Ancestry-specific GWASs were conducted in participants with European (n = 218 623) and African (n = 29 132) ancestry, then meta-analyzed (N = 247 755). Linkage-disequilibrium score regression was used to estimate single nucleotide variant (SNV)-heritability and genetic correlations (rg) with other alcohol and psychiatric traits. Genomic structural equation modeling (gSEM) was used to evaluate genetic associations between MaxAlc and other alcohol traits. Mendelian randomization was used to examine potential causal relationships between MaxAlc and liver enzyme levels. MTAG (multitrait analysis of GWAS) was used to analyze MaxAlc and problematic alcohol use (PAU) jointly.
Genetic associations.
MaxAlc was defined from the following survey item: "in a typical month, what is/was the largest number of drinks of alcohol you may have had in one day?" with ordinal responses from 0 to 15 or more drinks.
GWASs were conducted on sample sizes of as many as 247 455 US veterans. Participants were 92.68% male and had mean (SD) age of 65.92 (11.70) years. The MaxAlc GWAS resulted in 15 genome-wide significant loci. Top associations in European-ancestry and African-ancestry participants were with known functional variants in the ADH1B gene, namely rs1229984 (P = 3.12 × 10-101) and rs2066702 (P = 6.30 × 10-17), respectively. Novel associations were also found. SNV-heritability was 6.65% (SE, 0.41) in European-ancestry participants and 3.42% (SE, 1.46) in African-ancestry participants. MaxAlc was positively correlated with PAU (rg = 0.79; P = 3.95 × 10-149) and AUD (rg = 0.76; P = 1.26 × 10-127) and had negative rg with the UK Biobank "alcohol usually taken with meals" (rg = -0.53; P = 1.40 × 10-50). For psychiatric traits, MaxAlc had the strongest genetic correlation with suicide attempt (rg = 0.40; P = 3.02 × 10-21). gSEM supported a 2-factor model with MaxAlc loading on a factor with PAU and AUD and other alcohol consumption measures loading on a separate factor. Mendelian randomization supported an association between MaxAlc and the liver enzyme gamma-glutamyltransferase (β = 0.012; P = 2.66 × 10-10). MaxAlc MTAG resulted in 31 genome-wide significant loci.
The findings suggest that MaxAlc closely aligns genetically with PAU traits. This study improves understanding of the mechanisms associated with normative alcohol consumption vs problematic habitual use and AUD as well as how MaxAlc relates to psychiatric and medical conditions genetically and biologically.
The global endemic of cardiovascular diseases calls for improved risk assessment and treatment. Here, we describe an association between myocardial infarction (MI) and a common sequence variant on ...chromosome 9p21. This study included a total of 4587 cases and 12,767 controls. The identified variant, adjacent to the tumor suppressor genes CDKN2A and CDKN2B, was associated with the disease with high significance. Approximately 21% of individuals in the population are homozygous for this variant, and their estimated risk of suffering myocardial infarction is 1.64 times as great as that of noncarriers. The corresponding risk is 2.02 times as great for early-onset cases. The population attributable risk is 21% for MI in general and 31% for early-onset cases.
ABSTRACT
Endometriosis is a chronic gynecologic disease that causes pelvic pain and is often seen in association with depression and anxiety. The association with these mental health conditions was ...previously linked to chronic pain, although some evidence suggests this is not the sole factor. A genetic correlation has shown a potential causal effect of depression on endometriosis; however, further analyses are needed to determine whether pleiotropy observed is due to cause-effect relationships or to shared biological pathways.
This genetic association study (GWAS) aimed to conduct phenotypic and genetic association analyses on the comorbidity of endometriosis with depression, anxiety, and eating disorders. Individual-level data were obtained from the UK Biobank (UKB) and combined with genome-wide association statistics from data sets including the Psychiatric Genomics Consortium, the Million Veteran Program, the FinnGen study (Finland), and the CHARGE consortium. Individuals with endometriosis were identified by the
International Classification of Diseases Tenth Revision
codes as well as self-reported diagnoses from UKB surveys, and individuals with depression, anxiety, and eating disorders were identified using the
International Classification of Diseases Tenth Revision
codes. Logistic regression models were used to evaluate the association, and bidirectional 1-sample Mendelian randomization was used to test causal associations between endometriosis and anxiety, depression, and eating disorders. The GWAS studies were conducted for each of the mental health disorders being studied, and the Scalable Genetic Correlation Estimator (SCORE) method was used to compute single-nucleotide variant (SNV)–based heritability and genetic correlation from individual genotype and phenotype data. The linkage disequilibrium score regression method was used to calculate SNV-based heritability and genetic correlation using GWAS data.
A total of 8276 participants with endometriosis (mean age, 53.1 years) and 194,000 controls (mean age, 56.7 years) were included in this analysis. Regression models accounting for demographic and obstetric covariates, as well as psychiatric comorbidities, found endometriosis to be associated with increased odds of depression (odds ratio OR, 3.61; 95% confidence interval CI, 3.32–3.92), eating disorders (OR, 2.94; 95% CI, 1.96–4.41), and anxiety (OR, 2.61; 95% CI, 2.30–2.97). The GWAS studies showed endometriosis to be correlated with depression (genetic correlation rg = 0.36,
P
= 1.5 × 10
−9
), anxiety (rg = 0.33,
P
= 1.17 × 10
−5
), and eating disorders (
r
= 0.61,
P
= 0.03). The SCORE analysis of UKB phenotypic and genetic data calculated female-specific SNV-based heritability (SNV-h
2
) for endometriosis (mean SE SNV-h
2
, 0.086 0.015), depression (SNV-h
2
, 0.019 0.003), anxiety (SNV-h
2
, 0.012 0.002), and eating disorders (SNV-h
2
, 0.004 0.002). When applying linkage disequilibrium score regression to UKB genome-wide association statistics, endometriosis showed a consistent genetic correlation with anxiety (rg = 0.36,
P
= 3 × 10
−4
) and depression (rg = 0.34,
P
= 1 × 10
−5
). Mendelian randomization found significant associations for depression (OR, 1.09; 95% CI, 1.08–1.11) and anxiety (OR, 1.39; 95% CI, 1.13–1.65) with endometriosis, but no association with eating disorders (OR, 0.73; 95% CI, 0.04–1.43) was observed. Only the pleiotropic variant
DGKB
rs12666606 between endometriosis and depression survived genome-wide multiple testing correction.
The results of this GWAS show that eating disorders, depression, and anxiety are all associated with endometriosis and that genetic correlations were in line with phenotypic associations.
Variants of the gene ALOX5AP (also known as FLAP) encoding arachidonate 5-lipoxygenase activating protein are known to be associated with risk of myocardial infarction. Here we show that a haplotype ...(HapK) spanning the LTA4H gene encoding leukotriene A4 hydrolase, a protein in the same biochemical pathway as ALOX5AP, confers modest risk of myocardial infarction in an Icelandic cohort. Measurements of leukotriene B4 (LTB4) production suggest that this risk is mediated through upregulation of the leukotriene pathway. Three cohorts from the United States also show that HapK confers a modest relative risk (1.16) in European Americans, but it confers a threefold larger risk in African Americans. About 27% of the European American controls carried at least one copy of HapK, as compared with only 6% of African American controls. Our analyses indicate that HapK is very rare in Africa and that its occurrence in African Americans is due to European admixture. Interactions with other genetic or environmental risk factors that are more common in African Americans are likely to account for the greater relative risk conferred by HapK in this group.
Eosinophils are pleiotropic multifunctional leukocytes involved in initiation and propagation of inflammatory responses and thus have important roles in the pathogenesis of inflammatory diseases. ...Here we describe a genome-wide association scan for sequence variants affecting eosinophil counts in blood of 9,392 Icelanders. The most significant SNPs were studied further in 12,118 Europeans and 5,212 East Asians. SNPs at 2q12 (rs1420101), 2q13 (rs12619285), 3q21 (rs4857855), 5q31 (rs4143832) and 12q24 (rs3184504) reached genome-wide significance (P = 5.3 × 10−14, 5.4 × 10−10, 8.6 × 10−17, 1.2 × 10−10 and 6.5 × 10−19, respectively). A SNP at IL1RL1 associated with asthma (P = 5.5 × 10−12) in a collection of ten different populations (7,996 cases and 44,890 controls). SNPs at WDR36, IL33 and MYB that showed suggestive association with eosinophil counts were also associated with atopic asthma (P = 4.2 × 10−6, 2.2 × 10−5 and 2.4 × 10−4, respectively). We also found that a nonsynonymous SNP at 12q24, in SH2B3, associated significantly (P = 8.6 × 10−8) with myocardial infarction in six different populations (6,650 cases and 40,621 controls).
Problematic alcohol use (PAU), a trait that combines alcohol use disorder and alcohol-related problems assessed with a questionnaire, is a leading cause of death and morbidity worldwide. Here we ...conducted a large cross-ancestry meta-analysis of PAU in 1,079,947 individuals (European, N = 903,147; African, N = 122,571; Latin American, N = 38,962; East Asian, N = 13,551; and South Asian, N = 1,716 ancestries). We observed a high degree of cross-ancestral similarity in the genetic architecture of PAU and identified 110 independent risk variants in within- and cross-ancestry analyses. Cross-ancestry fine mapping improved the identification of likely causal variants. Prioritizing genes through gene expression and chromatin interaction in brain tissues identified multiple genes associated with PAU. We identified existing medications for potential pharmacological studies by a computational drug repurposing analysis. Cross-ancestry polygenic risk scores showed better performance of association in independent samples than single-ancestry polygenic risk scores. Genetic correlations between PAU and other traits were observed in multiple ancestries, with other substance use traits having the highest correlations. This study advances our knowledge of the genetic etiology of PAU, and these findings may bring possible clinical applicability of genetics insights-together with neuroscience, biology and data science-closer.
Most genome-wide association studies (GWAS) of major depression (MD) have been conducted in samples of European ancestry. Here we report a multi-ancestry GWAS of MD, adding data from 21 cohorts with ...88,316 MD cases and 902,757 controls to previously reported data. This analysis used a range of measures to define MD and included samples of African (36% of effective sample size), East Asian (26%) and South Asian (6%) ancestry and Hispanic/Latin American participants (32%). The multi-ancestry GWAS identified 53 significantly associated novel loci. For loci from GWAS in European ancestry samples, fewer than expected were transferable to other ancestry groups. Fine mapping benefited from additional sample diversity. A transcriptome-wide association study identified 205 significantly associated novel genes. These findings suggest that, for MD, increasing ancestral and global diversity in genetic studies may be particularly important to ensure discovery of core genes and inform about transferability of findings.
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