Aberrant connectivity of large-scale brain networks has been observed among individuals with alcohol use disorders (AUDs) as well as in those at risk, suggesting deficits in neural communication between brain regions in the liability to develop AUD. Electroencephalographical (EEG) coherence, which measures the degree of synchrony between brain regions, may be a useful measure of connectivity patterns in neural networks for studying the genetics of AUD. In 8810 individuals (6644 of European and 2166 of African ancestry) from the Collaborative Study on the Genetics of Alcoholism (COGA), we performed a Multi-Trait Analyses of genome-wide association studies (MTAG) on parietal resting-state theta (3-7 Hz) EEG coherence, which previously have been associated with AUD. We also examined developmental effects of GWAS findings on trajectories of neural connectivity in a longitudinal subsample of 2316 adolescent/young adult offspring from COGA families (ages 12-30) and examined the functional and clinical significance of GWAS variants. Six correlated single nucleotide polymorphisms located in a brain-expressed lincRNA (ENSG00000266213) on chromosome 18q23 were associated with posterior interhemispheric low theta EEG coherence (3-5 Hz). These same variants were also associated with alcohol use behavior and posterior corpus callosum volume, both in a subset of COGA and in the UK Biobank. Analyses in the subsample of COGA offspring indicated that the association of rs12954372 with low theta EEG coherence occurred only in females, most prominently between ages 25 and 30 (p < 2 × 10-9). Converging data provide support for the role of genetic variants on chromosome 18q23 in regulating neural connectivity and alcohol use behavior, potentially via dysregulated myelination. While findings were less robust, genome-wide associations were also observed with rs151174000 and parieto-frontal low theta coherence, rs14429078 and parieto-occipital interhemispheric high theta coherence, and rs116445911 with centro-parietal low theta coherence. These novel genetic findings highlight the utility of the endophenotype approach in enhancing our understanding of mechanisms underlying addiction susceptibility.

BACKGROUND: Many loci have been found to be associated with risk of epithelial ovarian cancer (EOC). However, although there is considerable variation in progression-free survival (PFS), no loci have been found to be associated with outcome at genome-wide levels of significance. METHODS: We carried out a genome-wide association study (GWAS) of PFS in 2,352 women with EOC who had undergone cytoreductive surgery and standard carboplatin/paclitaxel chemotherapy. RESULTS: We found seven SNPs at 12q24.33 associated with PFS (P < 5 × 10-8), the top SNP being rs10794418 (HR = 1.24; 95% CI, 1.15-1.34; P = 1.47 × 10-8). High expression of a nearby gene, ULK1, is associated with shorter PFS in EOC, and with poor prognosis in other cancers. SNP rs10794418 is also associated with expression of ULK1 in ovarian tumors, with the allele associated with shorter PFS being associated with higher expression, and chromatin interactions were detected between the ULK1 promoter and associated SNPs in serous and endometrioid EOC cell lines. ULK1 knockout ovarian cancer cell lines showed significantly increased sensitivity to carboplatin in vitro. CONCLUSIONS: The locus at 12q24.33 represents one of the first genome-wide significant loci for survival for any cancer. ULK1 is a plausible candidate for the target of this association. IMPACT: This finding provides insight into genetic markers associated with EOC outcome and potential treatment options.See related commentary by Peres and Monteiro, p. 1604.

Liver stiffness (LS) at sustained virological response (SVR) after direct-acting antivirals (DAA)-based therapy is a predictor of liver events in hepatitis C virus (HCV)-infected patients. The study aim was to identify genetic factors associated with LS changes from the moment of starting anti-HCV therapy to SVR. This prospective study included HCV-infected patients from the GEHEP-011 cohort who achieved SVR with DAA-based therapy, with LS pre-treatment ≥ 9.5 kPa and LS measurement available at SVR. Plink and Magma software were used to carry out genome-wide single-nucleotide polymorphism (SNP)-based and gene-based association analyses, respectively. The ShinyGO application was used for exploring enrichment in Gene Ontology (GO) categories for biological processes. Overall, 242 patients were included. Median (quartile 1, quartile 3) LS values at pre-treatment and at SVR were 16.8 (12, 28) kPa and 12.0 (8.5, 19.3) kPa, respectively. Thirty-five SNPs and three genes reached suggestive association with LS changes from the moment of starting anti-HCV therapy to SVR. GO categories related to DNA packaging complex, DNA conformation change, chromosome organization and chromatin organization were significantly enriched. Our study reports possible genetic factors associated with LS changes during HCV-infection cure. In addition, our results suggest that processes related to DNA conformation are also involved in these changes.

Genome-wide association studies (GWAS) of kidney function have uncovered hundreds of loci, primarily in populations of European ancestry. We have undertaken the first continental African GWAS of estimated glomerular filtration rate (eGFR), a measure of kidney function used to define chronic kidney disease (CKD). We conducted GWAS of eGFR in 3288 East Africans from the Uganda General Population Cohort (GPC) and replicated in 8224 African Americans from the Women's Health Initiative. Loci attaining genome-wide significant evidence for association (P < 5 × 10-8) were followed up with Bayesian fine-mapping to localize potential causal variants. The predictive power of a genetic risk score (GRS) constructed from previously reported trans-ancestry eGFR lead single nucleotide polymorphism (SNPs) was evaluated in the Uganda GPC. We identified and validated two eGFR loci. At the glycine amidinotransferase (GATM) locus, the association signal (lead SNP rs2433603, P = 1.0 × 10-8) in the Uganda GPC GWAS was distinct from previously reported signals at this locus. At the haemoglobin beta (HBB) locus, the association signal (lead SNP rs141845179, P = 3.0 × 10-8) has been previously reported. The lead SNP at the HBB locus accounted for 88% of the posterior probability of causality after fine-mapping, but did not colocalise with kidney expression quantitative trait loci. The trans-ancestry GRS of eGFR was not significantly predictive into the Ugandan population. In the first GWAS of eGFR in continental Africa, we validated two previously reported loci at GATM and HBB. At the GATM locus, the association signal was distinct from that previously reported. These results demonstrate the value of performing GWAS in continental Africans, providing a rich genomic resource to larger consortia for further discovery and fine-mapping. The study emphasizes that additional large-scale efforts in Africa are warranted to gain further insight into the genetic architecture of CKD.

Hypotension can affect cerebral perfusion and worsen cognitive outcomes. The prevalence of low blood pressure (BP) rises with increasing age. To our knowledge, no study has examined the genetic biomarkers for hypotension-related cognitive impairment (CI) yet. Utilizing the population-based genome-wide study of the Taiwan Biobank containing the data of 2533 healthy aging subjects, we found after adjustments for age, sex, education years, and principal components at a suggestive level of 1 × 10-5 that minor alleles of leucine rich repeat transmembrane neuronal 4 (LRRTM4) (rs13388459, rs1075716, rs62171995, rs17406146, rs2077823, and rs62170897), proprotein convertase subtilisin/kexin type 5 (PCSK5) (rs10521467), and the intergenic variation rs117129097 (the nearby gene: TMEM132C) are risk factors for CI in hypotensive subjects. Except for rs117129097, these single nucleotide polymorphisms (SNPs) were not markers per se for CI or for BP regulation. However, we found a suggestive interaction effect between each of the eight SNPs and hypotension on CI risk. In the hypotensive participants, those carrying minor alleles were associated with a higher incidence of CI in an additive manner than were those carrying major alleles (2 × 10-4 to 9 × 10-7). Intensive BP lowering in elderly patients carrying a minor allele of the eight identified SNPs should raise cautions to prevent a potential treatment-induced neurodegeneration.

To elucidate the genetics of coronary artery disease (CAD) in the Japanese population, we conducted a large-scale genome-wide association study of 168,228 individuals of Japanese ancestry (25,892 cases and 142,336 controls) with genotype imputation using a newly developed reference panel of Japanese haplotypes including 1,781 CAD cases and 2,636 controls. We detected eight new susceptibility loci and Japanese-specific rare variants contributing to disease severity and increased cardiovascular mortality. We then conducted a trans-ancestry meta-analysis and discovered 35 additional new loci. Using the meta-analysis results, we derived a polygenic risk score (PRS) for CAD, which outperformed those derived from either Japanese or European genome-wide association studies. The PRS prioritized risk factors among various clinical parameters and segregated individuals with increased risk of long-term cardiovascular mortality. Our data improve the clinical characterization of CAD genetics and suggest the utility of trans-ancestry meta-analysis for PRS derivation in non-European populations.

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers. Its poor prognosis is predominantly due to the fact that most patients remain asymptomatic until the disease reaches an advanced stage, alongside the lack of early markers and screening strategies. A better understanding of PDAC risk factors is essential for the identification of groups at high risk in the population. Genome-wide association studies (GWAS) have been a powerful tool for detecting genetic variants associated with complex traits, including pancreatic cancer. By exploiting functional and GWAS data, we investigated the associations between polymorphisms affecting gene function in the pancreas (expression quantitative trait loci, eQTLs) and PDAC risk. In a two-phase approach, we analysed 13 713 PDAC cases and 43 784 controls and identified a genome-wide significant association between the A allele of the rs2035875 polymorphism and increased PDAC risk (P = 7.14 × 10-10). This allele is known to be associated with increased expression in the pancreas of the keratin genes KRT8 and KRT18, whose increased levels have been reported to correlate with various tumour cell characteristics. Additionally, the A allele of the rs789744 variant was associated with decreased risk of developing PDAC (P = 3.56 × 10-6). This single nucleotide polymorphism is situated in the SRGAP1 gene and the A allele is associated with higher expression of the gene, which in turn inactivates the cyclin-dependent protein 42 (CDC42) gene expression, thus decreasing the risk of PDAC. In conclusion, we present here a functional-based novel PDAC risk locus and an additional strong candidate supported by significant associations and plausible biological mechanisms.

Increased serum uric acid (SUA) levels cause gout and are associated with multiple diseases, including chronic kidney disease. Previous genome-wide association studies (GWAS) have identified more than 180 loci that contribute to SUA levels. Here, we investigated genetic determinants of SUA level in the Korean population. We conducted a GWAS for SUA in 6,881 Korean individuals, calculated polygenic risk scores (PRSs) for common variants, and validated the association of low-frequency variants and PRS with SUA levels in 3,194 individuals. We identified two low-frequency and six common independent variants associated with SUA. Despite the overall similar effect sizes of variants in Korean and European populations, the proportion of variance for SUA levels explained by the variants was greater in the Korean population. A rare, nonsense variant SLC22A12 p.W258X showed the most significant association with reduced SUA levels, and PRSs of common variants associated with SUA levels were significant in multiple Korean cohorts. Interestingly, an East Asian-specific missense variant (rs671) in ALDH2 displayed a significant association on chromosome 12 with the SUA level. Further genetic epidemiological studies on SUA are needed in ethnically diverse cohorts to investigate rare or low-frequency variants and determine the influence of genetic and environmental factors on SUA.

OBJECTIVE: Systemic lupus erythematosus (SLE), an autoimmune disorder, has been associated with nearly 100 susceptibility loci. Nevertheless, these loci only partially explain SLE heritability and their putative causal variants are rarely prioritised, which make challenging to elucidate disease biology. To detect new SLE loci and causal variants, we performed the largest genome-wide meta-analysis for SLE in East Asian populations. METHODS: We newly genotyped 10 029 SLE cases and 180 167 controls and subsequently meta-analysed them jointly with 3348 SLE cases and 14 826 controls from published studies in East Asians. We further applied a Bayesian statistical approach to localise the putative causal variants for SLE associations. RESULTS: We identified 113 genetic regions including 46 novel loci at genome-wide significance (p<5×10-8). Conditional analysis detected 233 association signals within these loci, which suggest widespread allelic heterogeneity. We detected genome-wide associations at six new missense variants. Bayesian statistical fine-mapping analysis prioritised the putative causal variants to a small set of variants (95% credible set size ≤10) for 28 association signals. We identified 110 putative causal variants with posterior probabilities ≥0.1 for 57 SLE loci, among which we prioritised 10 most likely putative causal variants (posterior probability ≥0.8). Linkage disequilibrium score regression detected genetic correlations for SLE with albumin/globulin ratio (rg=-0.242) and non-albumin protein (rg=0.238). CONCLUSION: This study reiterates the power of large-scale genome-wide meta-analysis for novel genetic discovery. These findings shed light on genetic and biological understandings of SLE.

BACKGROUND: The genetic basis of lacunar stroke is poorly understood, with a single locus on 16q24 identified to date. We sought to identify novel associations and provide mechanistic insights into the disease. METHODS: We did a pooled analysis of data from newly recruited patients with an MRI-confirmed diagnosis of lacunar stroke and existing genome-wide association studies (GWAS). Patients were recruited from hospitals in the UK as part of the UK DNA Lacunar Stroke studies 1 and 2 and from collaborators within the International Stroke Genetics Consortium. Cases and controls were stratified by ancestry and two meta-analyses were done: a European ancestry analysis, and a transethnic analysis that included all ancestry groups. We also did a multi-trait analysis of GWAS, in a joint analysis with a study of cerebral white matter hyperintensities (an aetiologically related radiological trait), to find additional genetic associations. We did a transcriptome-wide association study (TWAS) to detect genes for which expression is associated with lacunar stroke; identified significantly enriched pathways using multi-marker analysis of genomic annotation; and evaluated cardiovascular risk factors causally associated with the disease using mendelian randomisation. FINDINGS: Our meta-analysis comprised studies from Europe, the USA, and Australia, including 7338 cases and 254 798 controls, of which 2987 cases (matched with 29 540 controls) were confirmed using MRI. Five loci (ICA1L-WDR12-CARF-NBEAL1, ULK4, SPI1-SLC39A13-PSMC3-RAPSN, ZCCHC14, ZBTB14-EPB41L3) were found to be associated with lacunar stroke in the European or transethnic meta-analyses. A further seven loci (SLC25A44-PMF1-BGLAP, LOX-ZNF474-LOC100505841, FOXF2-FOXQ1, VTA1-GPR126, SH3PXD2A, HTRA1-ARMS2, COL4A2) were found to be associated in the multi-trait analysis with cerebral white matter hyperintensities (n=42 310). Two of the identified loci contain genes (COL4A2 and HTRA1) that are involved in monogenic lacunar stroke. The TWAS identified associations between the expression of six genes (SCL25A44, ULK4, CARF, FAM117B, ICA1L, NBEAL1) and lacunar stroke. Pathway analyses implicated disruption of the extracellular matrix, phosphatidylinositol 5 phosphate binding, and roundabout binding (false discovery rate <0·05). Mendelian randomisation analyses identified positive associations of elevated blood pressure, history of smoking, and type 2 diabetes with lacunar stroke. INTERPRETATION: Lacunar stroke has a substantial heritable component, with 12 loci now identified that could represent future treatment targets. These loci provide insights into lacunar stroke pathogenesis, highlighting disruption of the vascular extracellular matrix (COL4A2, LOX, SH3PXD2A, GPR126, HTRA1), pericyte differentiation (FOXF2, GPR126), TGF-β signalling (HTRA1), and myelination (ULK4, GPR126) in disease risk. FUNDING: British Heart Foundation.