Prior Genome-wide Association Studies Research Articles

Transferability of Alzheimer Disease Polygenic Risk Score Across Populations and Its Association With Alzheimer Disease-Related Phenotypes

Polygenic risk scores (PRSs), which aggregate the genetic effects of single-nucleotide variants identified in genome-wide association studies (GWASs), can help distinguish individuals at a high genetic risk for Alzheimer disease (AD). However, genetic studies have predominantly focused on populations of European ancestry. To evaluate the transferability of a PRS for AD in the Korean population using summary statistics from a prior GWAS of European populations. This cohort study developed a PRS based on the summary statistics of a large-scale GWAS of a European population (the International Genomics of Alzheimer Project; 21 982 AD cases and 41 944 controls). This PRS was tested for an association with AD dementia and its related phenotypes in 1634 Korean individuals, who were recruited from 2013 to 2019. The association of a PRS based on a GWAS of a Japanese population (the National Center for Geriatrics and Gerontology; 3962 AD cases and 4074 controls) and a transancestry meta-analysis of European and Japanese GWASs was also evaluated. Data were analyzed from December 2020 to June 2021. Risk of AD dementia, amnestic mild cognitive impairment (aMCI), earlier symptom onset, and amyloid β deposition (Aβ). A total of 1634 Korean patients (969 women [59.3%]), including 716 individuals (43.6%) with AD dementia, 222 (13.6%) with aMCI, and 699 (42.8%) cognitively unimpaired controls, were analyzed in this study. The mean (SD) age of the participants was 71.6 (9.0) years. Higher PRS was associated with a higher risk of AD dementia independent of APOE ɛ4 status in the Korean population (OR, 1.95; 95% CI, 1.40-2.72; P < .001). Furthermore, PRS was associated with aMCI, earlier symptom onset, and Aβ deposition independent of APOE ɛ4 status. The PRS based on a transancestry meta-analysis of data sets comprising 2 distinct ancestries showed a slightly improved accuracy. In this cohort study, a PRS derived from a European GWAS identified individuals at a high risk for AD dementia in the Korean population. These findings emphasize the transancestry transferability and clinical value of PRSs and suggest the importance of enriching diversity in genetic studies of AD.

Integrative Genomics Analysis Implicates Decreased FGD6 Expression Underlying Risk of Intracranial Aneurysm Rupture

BACKGROUND: The genetic determinants and mechanisms underlying intracranial aneurysm rupture (rIA) are largely unknown. Given the ∼50% mortality rate of rIA, approaches to identify patients at high risk will inform screening, diagnostic, and preventative measures. OBJECTIVE: To identify and characterize the genetic basis of rIA. METHODS: We perform a genome-wide association study (GWAS) using functional genomics approaches to identify and characterize rIA-associated loci and genes. We perform a meta-analysis across 24 published GWAS of rIA. Single nucleotide polymorphisms, gene-burden analysis, and functional genomics identify and characterize genetic risk factors for rIA. RESULTS: Our cohort contains 84 353 individuals (7843 rIA cases and 76 510 controls). We identify 5 independent genetic loci reaching genome-wide significance (P &lt; 5.0 × 10−8) for rIA including rs12310399 (FGD6, odds ratio = 1.16), which has been implicated in prior GWAS of IA. We then quantified gene-level mutation burden across ∼20 000 genes, and only FGD6 (containing 21 rIA-associated single nucleotide polymorphisms) reached transcriptome-wide significance. Expression quantitative trait loci mapping indicates that rs12310399 causes decreased FGD6 gene expression in arterial tissue. Next, we used publicly available single-cell RNA sequencing of normal human cerebrovascular cells obtained during resection surgery and identify high expression of FGD6 in 1 of 3 arterial lineages but absent in perivascular cells. These data suggest how alterations in FGD6 may confer risk to rIA. CONCLUSION: We identify and characterize a known risk loci for IA, but not for rIA, containing FGD6. Elucidation of high-risk genetic loci may instruct population-genetic screening and clinical-genetic testing strategies to identify patients predisposed to rIA.

Whole genome DNA and RNA sequencing of whole blood elucidates the genetic architecture of gene expression underlying a wide range of diseases

To create a scientific resource of expression quantitative trail loci (eQTL), we conducted a genome-wide association study (GWAS) using genotypes obtained from whole genome sequencing (WGS) of DNA and gene expression levels from RNA sequencing (RNA-seq) of whole blood in 2622 participants in Framingham Heart Study. We identified 6,778,286 cis-eQTL variant-gene transcript (eGene) pairs at p < 5 × 10–8 (2,855,111 unique cis-eQTL variants and 15,982 unique eGenes) and 1,469,754 trans-eQTL variant-eGene pairs at p < 1e−12 (526,056 unique trans-eQTL variants and 7233 unique eGenes). In addition, 442,379 cis-eQTL variants were associated with expression of 1518 long non-protein coding RNAs (lncRNAs). Gene Ontology (GO) analyses revealed that the top GO terms for cis-eGenes are enriched for immune functions (FDR < 0.05). The cis-eQTL variants are enriched for SNPs reported to be associated with 815 traits in prior GWAS, including cardiovascular disease risk factors. As proof of concept, we used this eQTL resource in conjunction with genetic variants from public GWAS databases in causal inference testing (e.g., COVID-19 severity). After Bonferroni correction, Mendelian randomization analyses identified putative causal associations of 60 eGenes with systolic blood pressure, 13 genes with coronary artery disease, and seven genes with COVID-19 severity. This study created a comprehensive eQTL resource via BioData Catalyst that will be made available to the scientific community. This will advance understanding of the genetic architecture of gene expression underlying a wide range of diseases.

Host variation in type I interferon signaling genes (MX1), C-C chemokine receptor type 5 gene, and major histocompatibility complex class I alleles in treated HIV+ noncontrollers predict viral reservoir size.

Prior genomewide association studies have identified variation in major histocompatibility complex (MHC) class I alleles and C-C chemokine receptor type 5 gene (CCR5Δ32) as genetic predictors of viral control, especially in 'elite' controllers, individuals who remain virally suppressed in the absence of therapy. Cross-sectional genomewide association study. We analyzed custom whole exome sequencing and direct human leukocyte antigen (HLA) typing from 202 antiretroviral therapy (ART)-suppressed HIV+ noncontrollers in relation to four measures of the peripheral CD4+ T-cell reservoir: HIV intact DNA, total (t)DNA, unspliced (us)RNA, and RNA/DNA. Linear mixed models were adjusted for potential covariates including age, sex, nadir CD4+ T-cell count, pre-ART HIV RNA, timing of ART initiation, and duration of ART suppression. Previously reported 'protective' host genetic mutations related to viral setpoint (e.g. among elite controllers) were found to predict smaller HIV reservoir size. The HLA 'protective' B∗57:01 was associated with significantly lower HIV usRNA (q = 3.3 × 10-3), and among the largest subgroup, European ancestry individuals, the CCR5Δ32 deletion was associated with smaller HIV tDNA (P = 4.3 × 10-3) and usRNA (P = 8.7 × 10-3). In addition, genomewide analysis identified several single nucleotide polymorphisms in MX1 (an interferon stimulated gene) that were significantly associated with HIV tDNA (q = 0.02), and the direction of these associations paralleled MX1 gene eQTL expression. We observed a significant association between previously reported 'protective' MHC class I alleles and CCR5Δ32 with the HIV reservoir size in noncontrollers. We also found a novel association between MX1 and HIV total DNA (in addition to other interferon signaling relevant genes, PPP1CB, DDX3X). These findings warrant further investigation in future validation studies.

Common Variants Near ZIC1 and ZIC4 in Autopsy-Confirmed Multiple System Atrophy.

Multiple System Atrophy is a rare neurodegenerative disease with alpha-synuclein aggregation in glial cytoplasmic inclusions and either predominant olivopontocerebellar atrophy or striatonigral degeneration, leading to dysautonomia, parkinsonism, and cerebellar ataxia. One prior genome-wide association study in mainly clinically diagnosed patients with Multiple System Atrophy failed to identify genetic variants predisposing for the disease. Since the clinical diagnosis of Multiple System Atrophy yields a high rate of misdiagnosis when compared to the neuropathological gold standard, we studied only autopsy-confirmed cases. We studied common genetic variations in Multiple System Atrophy cases (N=731) and controls (N=2898). The most strongly disease-associated markers were rs16859966 on chromosome 3, rs7013955 on chromosome 8, and rs116607983 on chromosome 4 with P-values below 5 × 10-6 , all of which were supported by at least one additional genotyped and several imputed single nucleotide polymorphisms. The genes closest to the chromosome 3 locus are ZIC1 and ZIC4 encoding the zinc finger proteins of cerebellum 1 and 4 (ZIC1 and ZIC4). Since mutations of ZIC1 and ZIC4 and paraneoplastic autoantibodies directed against ZIC4 are associated with severe cerebellar dysfunction, we conducted immunohistochemical analyses in brain tissue of the frontal cortex and the cerebellum from 24 Multiple System Atrophy patients. Strong immunohistochemical expression of ZIC4 was detected in a subset of neurons of the dentate nucleus in all healthy controls and in patients with striatonigral degeneration, whereas ZIC4-immunoreactive neurons were significantly reduced inpatients with olivopontocerebellar atrophy. These findings point to a potential ZIC4-mediated vulnerability of neurons in Multiple System Atrophy. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Identifying genetic markers enriched by brain imaging endophenotypes in Alzheimer’s disease

BackgroundAlzheimer’s disease (AD) is a complex neurodegenerative disorder and the most common type of dementia. AD is characterized by a decline of cognitive function and brain atrophy, and is highly heritable with estimated heritability ranging from 60 to 80%. The most straightforward and widely used strategy to identify AD genetic basis is to perform genome-wide association study (GWAS) of the case-control diagnostic status. These GWAS studies have identified over 50 AD related susceptibility loci. Recently, imaging genetics has emerged as a new field where brain imaging measures are studied as quantitative traits to detect genetic factors. Given that many imaging genetics studies did not involve the diagnostic outcome in the analysis, the identified imaging or genetic markers may not be related or specific to the disease outcome.ResultsWe propose a novel method to identify disease-related genetic variants enriched by imaging endophenotypes, which are the imaging traits associated with both genetic factors and disease status. Our analysis consists of three steps: (1) map the effects of a genetic variant (e.g., single nucleotide polymorphism or SNP) onto imaging traits across the brain using a linear regression model, (2) map the effects of a diagnosis phenotype onto imaging traits across the brain using a linear regression model, and (3) detect SNP-diagnosis association via correlating the SNP effects with the diagnostic effects on the brain-wide imaging traits. We demonstrate the promise of our approach by applying it to the Alzheimer’s Disease Neuroimaging Initiative database. Among 54 AD related susceptibility loci reported in prior large-scale AD GWAS, our approach identifies 41 of those from a much smaller study cohort while the standard association approaches identify only two of those. Clearly, the proposed imaging endophenotype enriched approach can reveal promising AD genetic variants undetectable using the traditional method.ConclusionWe have proposed a novel method to identify AD genetic variants enriched by brain-wide imaging endophenotypes. This approach can not only boost detection power, but also reveal interesting biological pathways from genetic determinants to intermediate brain traits and to phenotypic AD outcomes.

An integrated genome and phenome-wide association study approach to understanding Alzheimer's disease predisposition

Genome-wide association studies (GWAS) have identified common single nucleotide polymorphisms (SNPs) that increase late-onset Alzheimer's disease (LOAD) risk. To identify additional LOAD-associated variants and provide insight into underlying disease biology, we performed a phenome-wide association study on 23 known LOAD-associated SNPs and 4:1 matched control SNPs using UK Biobank data. LOAD-associated SNPs were significantly enriched for associations with 8/778 queried traits, including 3 platelet traits. The strongest enrichment was for platelet distribution width (PDW) (p = 1.2 × 10−5), but increased PDW was not associated with LOAD susceptibility in Mendelian randomization analysis. Of 384 PDW-associated SNPs identified by prior GWAS, 36 were nominally associated with LOAD risk (17,008 cases; 37,154 controls) and 5 survived false-discovery rate correction. Associations confirmed known LOAD risk loci near PICALM, CD2AP, SPI1, and NDUFAF6, and identified a novel risk locus in epidermal growth factor receptor. Integrating GWAS and phenome-wide association study data reveals substantial pleiotropy between genetic determinants of LOAD and of platelet morphology, and for the first time implicates epidermal growth factor receptor – a mediator of β-amyloid toxicity – in Alzheimer's disease susceptibility.

Genetic Loci Associated With COVID-19 Positivity and Hospitalization in White, Black, and Hispanic Veterans of the VA Million Veteran Program.

SARS-CoV-2 has caused symptomatic COVID-19 and widespread death across the globe. We sought to determine genetic variants contributing to COVID-19 susceptibility and hospitalization in a large biobank linked to a national United States health system. We identified 19,168 (3.7%) lab-confirmed COVID-19 cases among Million Veteran Program participants between March 1, 2020, and February 2, 2021, including 11,778 Whites, 4,893 Blacks, and 2,497 Hispanics. A multi-population genome-wide association study (GWAS) for COVID-19 outcomes identified four independent genetic variants (rs8176719, rs73062389, rs60870724, and rs73910904) contributing to COVID-19 positivity, including one novel locus found exclusively among Hispanics. We replicated eight of nine previously reported genetic associations at an alpha of 0.05 in at least one population-specific or the multi-population meta-analysis for one of the four MVP COVID-19 outcomes. We used rs8176719 and three additional variants to accurately infer ABO blood types. We found that A, AB, and B blood types were associated with testing positive for COVID-19 compared with O blood type with the highest risk for the A blood group. We did not observe any genome-wide significant associations for COVID-19 severity outcomes among those testing positive. Our study replicates prior GWAS findings associated with testing positive for COVID-19 among mostly White samples and extends findings at three loci to Black and Hispanic individuals. We also report a new locus among Hispanics requiring further investigation. These findings may aid in the identification of novel therapeutic agents to decrease the morbidity and mortality of COVID-19 across all major ancestral populations.

Pleiotropy of Alzheimer’s Disease and Educational Attainment: Insights from the Summary Statistics

Epidemiological studies report beneficial associations of higher educational attainment (EDU) with Alzheimer’s disease (AD). Prior genome-wide association studies (GWAS) also reported variants associated with AD and EDU separately. The analysis of pleiotropic predisposition to these phenotypes may shed light on EDU-related protection against AD. We examined pleiotropic predisposition to AD and EDU using Fisher’s method and omnibus test applied to summary statistics for single nucleotide polymorphisms (SNPs) associated with AD and EDU in large-scale univariate GWAS at suggestive-effect (5×10-8

Pleiotropy of Alzheimer’s Disease and Educational Attainment: Insights from the Summary Statistics

Epidemiological studies report beneficial associations of higher educational attainment (EDU) with Alzheimer’s disease (AD). Prior genome-wide association studies (GWAS) also reported variants associated with AD and EDU separately. The analysis of pleiotropic predisposition to these phenotypes may shed light on EDU-related protection against AD. We examined pleiotropic predisposition to AD and EDU using Fisher’s method and omnibus test applied to summary statistics for single nucleotide polymorphisms (SNPs) associated with AD and EDU in large-scale univariate GWAS at suggestive-effect (5×10-8

Pleiotropic predisposition to Alzheimer's disease and educational attainment: insights from the summary statistics analysis.

Epidemiological studies report beneficial associations of higher educational attainment (EDU) with Alzheimer’s disease (AD). Prior genome-wide association studies (GWAS) also reported variants associated with AD and EDU separately. The analysis of pleiotropic associations with these phenotypes may shed light on EDU-related protection against AD. We performed pleiotropic meta-analyses using Fisher’s method and omnibus test applied to summary statistics for single nucleotide polymorphisms (SNPs) associated with AD and EDU in large-scale univariate GWAS at suggestive-effect (5 × 10−8 < p < 0.1) and genome-wide (p ≤ 5 × 10−8) significance levels. We report 53 SNPs that attained p ≤ 5 × 10−8 at least in one of the pleiotropic meta-analyses and were reported in the univariate GWAS at 5 × 10−8 < p < 0.1. Of them, there were 46 pleiotropic SNPs according to Fisher’s method. Additionally, Fisher’s method identified 25 of 206 SNPs with pleiotropic effects, which attained p ≤ 5 × 10−8 in the univariate GWAS. We showed that a large fraction of the pleiotropic associations was affected by a counterintuitive phenomenon of antagonistic genetic heterogeneity, which explains the increase, rather than decrease, of the significance of the pleiotropic associations in the omnibus test. Functional enrichment analysis showed that apart from cancers, gene set harboring the non-pleiotropic SNPs was characterized by late-onset AD and neurodevelopmental disorders. The pleiotropic gene set was characterized by a broad spectrum of progressive neurological and neuromuscular diseases and immune-mediated conditions, including progressive motor neuropathy, multiple sclerosis, Parkinson’s disease, and severe AD. Our results suggest that disentangling genes harboring variants with and without pleiotropic associations with AD and EDU is promising for dissecting heterogeneity in biological mechanisms of AD.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11357-021-00484-1.

Association between WWOX/MAF variants and dementia-related neuropathologic endophenotypes

The genetic locus containing the WWOX and MAF genes was implicated as a clinical Alzheimer's disease (AD) risk locus in two recent large meta-analytic genome wide association studies (GWAS). In a prior GWAS, we identified a variant in WWOX as a suggestive risk allele for hippocampal sclerosis. We hypothesized that the WWOX/MAF locus may be preferentially associated with non-plaque- and non-tau-related neuropathological changes (NC). Data from research participants with GWAS and autopsy measures from the National Alzheimer's Coordinating Center and the Religious Orders Study and the Rush Memory and Aging Project were meta-analyzed. Notably, no variants in the locus were significantly associated with ADNC. However, several WWOX/MAF variants had significant adjusted associations with limbic-predominant age-related TDP-43 encephalopathy NC (LATE-NC), HS, and brain arteriolosclerosis. These associations remained largely unchanged after adjustment for ADNC (operationalized with standard semiquantitative staging), suggesting that these associations are independent of ADNC. Thus, WWOX genetic variants were associated pathologically with LATE-NC, not ADNC.

Mendelian Randomization Focused Analysis of Vitamin D on the Secondary Prevention of Ischemic Stroke.

Experimental studies showed vitamin D (Vit-D) could promote vascular regeneration and repair. Prior randomized studies had focused mainly on primary prevention. Whether Vit-D protects against ischemic stroke and myocardial infarction recurrence among subjects with prior ischemic insults was unknown. Here, we dissected through Mendelian randomization any effect of Vit-D on the secondary prevention of recurrent ischemic stroke and myocardial infarction. Based on a genetic risk score for Vit-D constructed from a derivation cohort sample (n=5331, 45% Vit-D deficient, 89% genotyped) via high-throughput exome-chip screening of 12 prior genome-wide association study-identified genetic variants of Vit-D mechanistic pathways (rs2060793, rs4588, and rs7041; F statistic, 73; P<0.001), we performed a focused analysis on prospective recurrence of myocardial infarction (MI) and ischemic stroke in an independent subsample with established ischemic disease (n=441, all with prior first ischemic event; follow-up duration, 41.6±14.3 years) under a 2-sample, individual-data, prospective Mendelian randomization approach. In the ischemic disease subsample, 11.1% (n=49/441) had developed recurrent ischemic stroke or MI and 13.3% (n=58/441) had developed recurrent or de novo ischemic stroke/MI. Kaplan-Meier analyses showed that genetic risk score predicted improved event-free survival from recurrent ischemic stroke or MI (log-rank, 13.0; P=0.001). Cox regression revealed that genetic risk score independently predicted reduced risk of recurrent ischemic stroke or MI combined (hazards ratio, 0.62 [95% CI, 0.48-0.81]; P<0.001), after adjusted for potential confounders. Mendelian randomization supported that Vit-D is causally protective against the primary end points of recurrent ischemic stroke or MI (Wald estimate: odds ratio, 0.55 [95% CI, 0.35-0.81]) and any recurrent or de novo ischemic stroke/MI (odds ratio, 0.64 [95% CI, 0.42-0.91]) and recurrent MI alone (odds ratio, 0.52 [95% CI, 0.30-0.81]). Genetically predicted lowering in Vit-D level is causal for the recurrence of ischemic vascular events in persons with prior ischemic stroke or MI.

Multiethnic genome-wide and HLA association study of total serum IgE level

Total serum IgE (tIgE) is an important intermediate phenotype of allergic disease. Whole genome genetic association studies across ancestries may identify important determinants of IgE. We aimed to increase understanding of genetic variants affecting tIgE production across the ancestry and allergic disease spectrum by leveraging data from the National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine program; the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA); and the Atopic Dermatitis Research Network (N= 21,901). We performed genome-wide association within strata of study, disease, and ancestry groups, and we combined results via a meta-regression approach that models heterogeneity attributable to ancestry. We also tested for association between HLA alleles called from whole genome sequence data and tIgE, assessing replication of associations in HLA alleles called from genotype array data. We identified 6 loci at genome-wide significance (P< 5×10-9), including 4 loci previously reported as genome-wide significant for tIgE, as well as new regions in chr11q13.5 and chr15q22.2, which were also identified in prior genome-wide association studies of atopic dermatitis and asthma. In the HLA allele association study, HLA-A∗02:01 was associated with decreased tIgE level (Pdiscovery= 2×10-4; Preplication= 5×10-4; Pdiscovery+replication= 4×10-7), and HLA-DQB1∗03:02 was strongly associated with decreased tIgE level in Hispanic/Latino ancestry populations (PHispanic/Latino discovery+replication= 8×10-8). We performed the largest genome-wide association study and HLA association study of tIgE focused on ancestrally diverse populations and found several known tIgE and allergic disease loci that are relevant in non-European ancestry populations.

Increased risk of severe clinical course of COVID-19 in carriers of HLA-C*04:01.

BackgroundSince the beginning of the coronavirus disease 2019 (COVID-19) pandemic, there has been increasing urgency to identify pathophysiological characteristics leading to severe clinical course in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Human leukocyte antigen alleles (HLA) have been suggested as potential genetic host factors that affect individual immune response to SARS-CoV-2. We sought to evaluate this hypothesis by conducting a multicenter study using HLA sequencing.MethodsWe analyzed the association between COVID-19 severity and HLAs in 435 individuals from Germany (n = 135), Spain (n = 133), Switzerland (n = 20) and the United States (n = 147), who had been enrolled from March 2020 to August 2020. This study included patients older than 18 years, diagnosed with COVID-19 and representing the full spectrum of the disease. Finally, we tested our results by meta-analysing data from prior genome-wide association studies (GWAS).FindingsWe describe a potential association of HLA-C*04:01 with severe clinical course of COVID-19. Carriers of HLA-C*04:01 had twice the risk of intubation when infected with SARS-CoV-2 (risk ratio 1.5 [95% CI 1.1–2.1], odds ratio 3.5 [95% CI 1.9–6.6], adjusted p-value = 0.0074). These findings are based on data from four countries and corroborated by independent results from GWAS. Our findings are biologically plausible, as HLA-C*04:01 has fewer predicted bindings sites for relevant SARS-CoV-2 peptides compared to other HLA alleles.InterpretationHLA-C*04:01 carrier state is associated with severe clinical course in SARS-CoV-2. Our findings suggest that HLA class I alleles have a relevant role in immune defense against SARS-CoV-2.FundingFunded by Roche Sequencing Solutions, Inc.

Functional validation of a finding from a mouse genome-wide association study shows that Azi2 influences the acute locomotor stimulant response to methamphetamine.

In a previous genome-wide association study (GWAS) using outbred Carworth Farms White (CFW) mice, we identified a locus that influenced the stimulant response to methamphetamine and colocalized with an eQTL for Azi2. Based on those findings, we hypothesized that heritable differences in Azi2 expression were causally related to the differential response to methamphetamine. To test that hypothesis, we created a mutant Azi2 allele on an inbred C57BL/6J background. The mutant allele enhanced the locomotor response to methamphetamine. However, the GWAS had suggested that lower Azi2 would decrease the locomotor response to methamphetamine. We also sought to explore the mechanism by which Azi2 influenced methamphetamine sensitivity. A recent publication reported that the 3'UTR of Azi2 mRNA downregulates the expression of Slc6a3, which encodes the dopamine transporter, which is a key target of methamphetamine. We evaluated the relationship between Azi2, Azi2 3'UTR and Slc6a3 expression in the ventral tegmental area of wildtype, mutant Azi2 heterozygotes and mutant Azi2 homozygotes and in a new cohort of outbred CFW mice where both allele mapped in our prior GWAS were segregating. We did not observe any correlation between Azi2 and Slc6a3 in either cohort. However, RNA sequencing confirmed that the Azi2 mutation altered Azi2 expression and also revealed a number of potentially important genes and pathways that were regulated by Azi2, including the metabotropic glutamate receptor group III pathway and nicotinic acetylcholine receptor signaling pathway. Our results support a role for Azi2 in methamphetamine sensitivity; however, the exact mechanism does not appear to involve regulation of Slc6a3.

1129-P: The Genetic Architecture of Cardiovascular Disease in Individuals with Type 2 Diabetes

Background: Type 2 diabetes mellitus (T2DM) is a known risk factor for cardiovascular disease including coronary heart disease (CHD), stroke, and peripheral vascular disease (PVD). However, the genetic underpinnings of cardiovascular disease in those with T2DM is not well understood. Methods: Using 15 studies from dbGaP and the UK Biobank, we conducted the largest to date genome-wide association studies (GWAS) for CHD, stroke and PVD in up to 61,880 individuals with T2DM including 47,140 of European, 8,891 of African, 2,622 of Hispanic, 2,120 of South Asian and 1,107 of East Asian ancestry. GWAS were combined via ancestry-specific and transethnic meta-analyses with fixed-effects. Additional transethnic analysis with MR-MEGA was conducted to account for heterogeneity in allelic effects correlated with ancestry. Results: We replicated previously reported CHD associated loci at genome-wide significance (GW, p≤5×10-8) including 9p21, LPA, and PSRC1. Combining our results with those of prior CHD GWAS in T2DM revealed additional GW significant signals in known CHD loci: PHACTR1, ADAMTS7, HHIPL1, and LPL. European ancestry specific analysis confirmed prior GW significant associations between LPA and PHACTR1 loci and PVD. MR-MEGA analysis of PVD identified novel GW significant loci in CNST and AVPI1. We found a significant genetic correlation of 0.74 (SE= .27) between CHD and PVD. Transethnic analysis of stroke GWAS yielded no GW significant loci. However, African ancestry specific analysis yielded two novel GW signals in the NKAIN2 and BRF1 loci. A significant association between interleukin-6 signaling and stroke was identified using pathway analysis. Conclusions: Ancestry-specific and transethnic analysis of cardiovascular disease in T2DM confirmed prior CHD GWAS findings and revealed novel associations with PVD and stroke that warrant further investigation. Disclosure E. L. Richard: None. S. Cao: None. A. Shadyab: None. R. Salem: None. Funding National Institutes of Health

The Shared Genetic Architectures Between Lung Cancer and Multiple Polygenic Phenotypes in Genome-Wide Association Studies.

Prior genome-wide association studies have identified numerous lung cancer risk loci and reveal substantial etiologic heterogeneity across histologic subtypes. Analyzing the shared genetic architecture underlying variation in complex traits can elucidate common genetic etiologies across phenotypes. Exploring pairwise genetic correlations between lung cancer and other polygenic traits can reveal the common genetic etiology of correlated phenotypes. Using cross-trait linkage disequilibrium score regression, we estimated the pairwise genetic correlation and heritability between lung cancer and multiple traits using publicly available summary statistics. Identified genetic relationships were also examined after excluding genomic regions known to be associated with smoking behaviors, a major risk factor for lung cancer. We observed several traits showing moderate single nucleotide polymorphism-based heritability and significant genetic correlations with lung cancer. We observed highly significant correlations between the genetic architectures of lung cancer and emphysema/chronic bronchitis across all histologic subtypes, as well as among lung cancer occurring among smokers. Our analyses revealed highly significant positive correlations between lung cancer and paternal history of lung cancer. We also observed a strong negative correlation with parental longevity. We observed consistent directions in genetic patterns after excluding genomic regions associated with smoking behaviors. This study identifies numerous phenotypic traits that share genomic architecture with lung carcinogenesis and are not fully accounted for by known smoking-associated genomic loci. These findings provide new insights into the etiology of lung cancer by identifying traits that are genetically correlated with increased risk of lung cancer.

A genome-wide association study for shoulder impingement and rotator cuff disease.

The purpose of the study was to identify genetic variants associated with rotator cuff disease by performing a genome-wide association study (GWAS) for shoulder impingement using the UK Biobank (UKB) cohort and then combining the GWAS data with a prior GWAS for rotator cuff tears. The loci identified by the GWAS and meta-analysis were examined for changes in expression following rotator cuff tearing using RNA sequencing. A GWAS was performed using data from UKB with 3864 cases of shoulder impingement. The summary statistics from shoulder impingement and a prior study on rotator cuff tears were combined in a meta-analysis. Also, the previous association of 2 single-nucleotide polymorphisms (SNPs) with shoulder impingement from a published GWAS using the UKB was tested. Rotator cuff tendon biopsies were obtained from 24 patients with full-thickness rotator cuff tears who underwent arthroscopic rotator cuff repair (cases) and 9 patients who underwent open reduction internal fixation for a proximal humeral fracture (controls). Total RNA was extracted and differential gene expression was measured by RNA sequencing for genes with variants associated with rotator cuff tearing. The shoulder impingement GWAS identified 4 new loci: LOC100506457, LSP1P3, LOC100506207, and MIS18BP1/LINC00871. Combining data with a prior GWAS for rotator cuff tears in a meta-analysis resulted in the identification of an additional 7 loci: SLC39A8/UBE2D3, C5orf63, ASTN2, STK24, FRMPD4, ACOT9/SAT1, and LINC00890/ALG13. Many of the identified loci have known biologic functions or prior associations with diseases, suggesting possible biologic pathways leading to rotator cuff disease. RNA sequencing experiments show that expression of STK24 increases whereas expression of SAT1 and UBE2D3 decreases following rotator cuff tearing. Two SNPs previously reported to show an association with shoulder impingement from a prior UKB GWAS were not validated in our study. This is the first GWAS for shoulder impingement in which new data from UKB enabled the identification of 4 loci showing a genetic association. A meta-analysis with a prior GWAS for rotator cuff tearing identified an additional 7 loci. The known biologic roles of many of the 11 loci suggest plausible biologic mechanisms underlying the etiology of rotator cuff disease. The risk alleles from each of the genetic loci can be used to assess the risk for rotator cuff disease in individual patients, enabling preventative or restorative actions via personalized medicine.

Investigating the genetic architecture of noncognitive skills using GWAS-by-subtraction.

Little is known about the genetic architecture of traits affecting educational attainment other than cognitive ability. We used Genomic Structural Equation Modeling and prior genome-wide association studies (GWAS) of educational attainment (n = 1,131,881) and cognitive test performance (n = 257,841) to estimate SNP associations with educational attainment variation that is independent of cognitive ability.We identified 157 genome-wide significant loci and a polygenic architecture accounting for 57% of genetic variance in educational attainment. Non-cognitive genetics were enriched in the same brain tissues and cell types as cognitive performance but showed different associations with gray-matter brain volumes. Non-cognitive genetics were further distinguished by associations with personality traits, less risky behavior,and increased risk for certain psychiatric disorders.For socioeconomic success and longevity, non-cognitive and cognitive-performance genetics demonstrated similar-magnitude associations. By conducting a GWAS of a phenotype that was not directly measured, we offer a first view of genetic architecture of non-cognitive skills influencing educational success.