Renal cell carcinoma (RCC) represents between 80 and 90% of kidney cancers. Previous genome-wide association studies of RCC have identified five variants conferring risk of the disease. Here we report the results from a discovery RCC genome-wide association study and replication analysis, including a total of 2,411 patients and 71,497 controls. One variant, rs35252396[CG] located at 8q24.21, is significantly associated with RCC after combining discovery and replication results (OR=1.27, P(combined)=5.4 × 10(-11)) and has an average risk allele frequency in controls of 46%. rs35252396[CG] does not have any strongly correlated variants in the genome and is located within a region predicted to have regulatory functions in several cell lines, including six originating from the kidney. This is the first RCC variant reported at 8q24.21 and it is largely independent (r(2)≤0.02) of the numerous previously reported cancer risk variants at this locus.

OBJECTIVE: To discover genetic determinants of Parkinson disease (PD) motor subtypes, including tremor dominant (TD) and postural instability/gait difficulty (PIGD) forms. METHODS: In 3,212 PD cases of European ancestry, we performed a genome-wide association study (GWAS) examining 2 complementary outcome traits derived from the Unified Parkinson's Disease Rating Scale, including dichotomous motor subtype (TD vs PIGD) or a continuous tremor/PIGD score ratio. Logistic or linear regression models were adjusted for sex, age at onset, disease duration, and 5 ancestry principal components, followed by meta-analysis. RESULTS: Among 71 established PD risk variants, we detected multiple suggestive associations with PD motor subtype, including GPNMB (rs199351, p subtype = 0.01, p ratio = 0.03), SH3GL2 (rs10756907, p subtype = 0.02, p ratio = 0.01), HIP1R (rs10847864, p subtype = 0.02), RIT2 (rs12456492, p subtype = 0.02), and FBRSL1 (rs11610045, p subtype = 0.02). A PD genetic risk score integrating all 71 PD risk variants was also associated with subtype ratio (p = 0.026, ß = -0.04, 95% confidence interval = -0.07-0). Based on top results of our GWAS, we identify a novel suggestive association at the STK32B locus (rs2301857, p ratio = 6.6 × 10-7), which harbors an independent risk allele for essential tremor. CONCLUSIONS: Multiple PD risk alleles may also modify clinical manifestations to influence PD motor subtype. The discovery of a novel variant at STK32B suggests a possible overlap between genetic risk for essential tremor and tremor-dominant PD.

Although many genes that affect narcolepsy risk have been identified, the interactions among these genes are still unclear. Moreover, there is a lack of research on the construction of the genetic network of narcolepsy. To screen candidate genes related to the onset of narcolepsy type 1, the function and distribution of important genes related to narcolepsy type 1 were studied and a gene network was constructed to study the pathogenesis of narcolepsy type 1.A case-control study (observational study) of 1075 Chinese narcoleptic patients and 1997 controls was conducted. The gene-sequencing data was analyzed using genome-wide association analysis. The candidate genes related to narcolepsy were identified by differential gene expression analysis and literature research. Then, the 28 candidate genes were input into the KEGG database and 32 pathway data related to candidate genes were obtained. A gene network, with the pathways as links and the genes as nodes, was constructed. According to our results, TNF, MHC II, NFATC2, and CXCL8 were the top genes in the gene network.TNF, MHC II, NFATC2, and CXCL8 are closely related to narcolepsy type I and require further study. By analyzing the pathways of disease-related genes and the network of gene interaction, we can provide an outlinefor the study of specific mechanisms of and treatments for narcolepsy.

Kawasaki disease (KD) is a paediatric vasculitis associated with coronary artery aneurysms (CAA). Genetic variants influencing susceptibility to KD have been previously identified, but no risk alleles have been validated that influence CAA formation. We conducted a genome-wide association study (GWAS) for CAA in KD patients of European descent with 200 cases and 276 controls. A second GWAS for susceptibility pooled KD cases with healthy paediatric controls from vaccine trials in the UK (n = 1609). Logistic regression mixed models were used for both GWASs. The susceptibility GWAS was meta-analysed with 400 KD cases and 6101 controls from a previous European GWAS, these results were further meta-analysed with Japanese GWASs at two putative loci. The CAA GWAS identified an intergenic region of chromosome 20q13 with multiple SNVs showing genome-wide significance. The risk allele of the most associated SNV (rs6017006) was present in 13% of cases and 4% of controls; in East Asian 1000 Genomes data, the allele was absent or rare. Susceptibility GWAS with meta-analysis with previously published European data identified two previously associated loci (ITPKC and FCGR2A). Further meta-analysis with Japanese GWAS summary data from the CASP3 and FAM167A genomic regions validated these loci in Europeans showing consistent effects of the top SNVs in both populations. We identified a novel locus for CAA in KD patients of European descent. The results suggest that different genes determine susceptibility to KD and development of CAA and future work should focus on the function of the intergenic region on chromosome 20q13.

Thrombosis after liver transplantation substantially impairs graft- and patient survival. Inevitably, heritable disorders of coagulation originating in the donor liver are transmitted by transplantation. We hypothesized that genetic variants in donor thrombophilia genes are associated with increased risk of posttransplant thrombosis. We genotyped 775 donors for adult recipients and 310 donors for pediatric recipients transplanted between 1993 and 2018. We determined the association between known donor thrombophilia gene variants and recipient posttransplant thrombosis. In addition, we performed a genome-wide association study (GWAS) and meta-analyzed 1085 liver transplantations. In our donor cohort, known thrombosis risk loci were not associated with posttransplant thrombosis, suggesting that it is unnecessary to exclude liver donors based on thrombosis-susceptible polymorphisms. By performing a meta-GWAS from children and adults, we identified 280 variants in 55 loci at suggestive genetic significance threshold. Downstream prioritization strategies identified biologically plausible candidate genes, among which were AK4 (rs11208611-T, p = 4.22 × 10-05 ) which encodes a protein that regulates cellular ATP levels and concurrent activation of AMPK and mTOR, and RGS5 (rs10917696-C, p = 2.62 × 10-05 ) which is involved in vascular development. We provide evidence that common genetic variants in the donor, but not previously known thrombophilia-related variants, are associated with increased risk of thrombosis after liver transplantation.

Body composition (fat, skeletal muscle and bone mass) is an important determinant of overall health and risk of endocrine disorders such as type 2 diabetes and osteoporosis. Although diet and physical activity are strongly implicated, body composition is also heritable. We conducted a discovery genome-wide association study on 31 phenotypes from the three-compartment body composition model (fat, lean and bone mass) in a set of 4 386 individuals (n = 2 109 males, n = 2 294 females) from the UK Biobank pilot imaging enhancement program that underwent a dual energy X-ray absorptiometry (DXA) scan for assessment of body composition and genetic screening. From 6 137 607 imputed single nucleotide polymorphisms (SNPs) we identified 17 body composition loci (P<5.0 x 10-8). GWAS from the combined dataset identified four statistically significant SNPs (rs7592270, rs145972737, rs13212044, rs77772562). In sex-stratified GWAS, 10 male specific SNPs across all traits were identified and five female specific SNPs. Of the 17 SNPs, six were in or close to a gene where there was a plausible functional connection. Three SNPs (rs7592270, rs77772562 and rs7552312) were correlated with obesity phenotypes, one SNP (rs2236705) with lean phenotypes and two with bone mass phenotypes (rs112098641 and rs113380185). These results highlight candidate genes and biological pathways related to body composition, including glucose metabolism and estrogen regulation, that are of interest to replicate in future studies.

Socioeconomic status (SES) and education (EDU) are phenotypically associated with psychiatric disorders and behaviours. It remains unclear how these associations influence genetic risk for psychopathology, psychosocial factors and EDU and/or SES (EDU/SES) individually. Using information from >1 million individuals, we conditioned the genetic risk for psychiatric disorders, personality traits, brain imaging phenotypes and externalizing behaviours with genome-wide data for EDU/SES. Accounting for EDU/SES significantly affected the observed heritability of psychiatric traits, ranging from 2.44% h2 decrease for bipolar disorder to 14.2% h2 decrease for Tourette syndrome. Neuroticism h2 significantly increased by 20.23% after conditioning with SES. After EDU/SES conditioning, neuronal cell types were identified for risky behaviour (excitatory), major depression (inhibitory), schizophrenia (excitatory and γ-aminobutyric acid (GABA) mediated) and bipolar disorder (excitatory). Conditioning with EDU/SES also revealed unidirectional causality between brain morphology, psychopathology and psychosocial factors. Our results indicate that genetic discoveries related to psychopathology and psychosocial factors may be limited by genetic overlap with EDU/SES.

Brain-derived neurotrophic factor (BDNF) plays an important role in brain development and function. Substantial amounts of BDNF are present in peripheral blood, and may serve as biomarkers for Alzheimer's disease incidence as well as targets for intervention to reduce Alzheimer's disease risk. With the exception of the genetic polymorphism in the BDNF gene, Val66Met, which has been extensively studied with regard to neurodegenerative diseases, the genetic variation that influences circulating BDNF levels is unknown. We aimed to explore the genetic determinants of circulating BDNF levels in order to clarify its mechanistic involvement in brain structure and function and Alzheimer's disease pathophysiology in middle-aged and old adults. Thus, we conducted a meta-analysis of genome-wide association study of circulating BDNF in 11 785 middle- and old-aged individuals of European ancestry from the Age, Gene/Environment Susceptibility-Reykjavik Study (AGES), the Framingham Heart Study (FHS), the Rotterdam Study and the Study of Health in Pomerania (SHIP-Trend). Furthermore, we performed functional annotation analysis and related the genetic polymorphism influencing circulating BDNF to common Alzheimer's disease pathologies from brain autopsies. Mendelian randomization was conducted to examine the possible causal role of circulating BDNF levels with various phenotypes including cognitive function, stroke, diabetes, cardiovascular disease, physical activity and diet patterns. Gene interaction networks analysis was also performed. The estimated heritability of BDNF levels was 30% (standard error = 0.0246, P-value = 4 × 10-48). We identified seven novel independent loci mapped near the BDNF gene and in BRD3, CSRNP1, KDELC2, RUNX1 (two single-nucleotide polymorphisms) and BDNF-AS. The expression of BDNF was associated with neurofibrillary tangles in brain tissues from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP). Seven additional genes (ACAT1, ATM, NPAT, WDR48, TTC21A, SCN114 and COX7B) were identified through expression and protein quantitative trait loci analyses. Mendelian randomization analyses indicated a potential causal role of BDNF in cardioembolism. Lastly, Ingenuity Pathway Analysis placed circulating BDNF levels in four major networks. Our study provides novel insights into genes and molecular pathways associated with circulating BDNF levels and highlights the possible involvement of plaque instability as an underlying mechanism linking BDNF with brain neurodegeneration. These findings provide a foundation for a better understanding of BDNF regulation and function in the context of brain aging and neurodegenerative pathophysiology.

Current genome-wide association studies do not yet capture sufficient diversity in populations and scope of phenotypes. To expand an atlas of genetic associations in non-European populations, we conducted 220 deep-phenotype genome-wide association studies (diseases, biomarkers and medication usage) in BioBank Japan (n = 179,000), by incorporating past medical history and text-mining of electronic medical records. Meta-analyses with the UK Biobank and FinnGen (ntotal = 628,000) identified ~5,000 new loci, which improved the resolution of the genomic map of human traits. This atlas elucidated the landscape of pleiotropy as represented by the major histocompatibility complex locus, where we conducted HLA fine-mapping. Finally, we performed statistical decomposition of matrices of phenome-wide summary statistics, and identified latent genetic components, which pinpointed responsible variants and biological mechanisms underlying current disease classifications across populations. The decomposed components enabled genetically informed subtyping of similar diseases (for example, allergic diseases). Our study suggests a potential avenue for hypothesis-free re-investigation of human diseases through genetics.

Frozen shoulder is a painful condition that often requires surgery and affects up to 5% of individuals aged 40-60 years. Little is known about the causes of the condition, but diabetes is a strong risk factor. To begin to understand the biological mechanisms involved, we aimed to identify genetic variants associated with frozen shoulder and to use Mendelian randomization to test the causal role of diabetes. We performed a genome-wide association study (GWAS) of frozen shoulder in the UK Biobank using data from 10,104 cases identified from inpatient, surgical and primary care codes. We used data from FinnGen for replication and meta-analysis. We used one-sample and two-sample Mendelian randomization approaches to test for a causal association of diabetes with frozen shoulder. We identified five genome-wide significant loci. The most significant locus (lead SNP rs28971325; OR = 1.20, [95% CI: 1.16-1.24], p = 5x10-29) contained WNT7B. This variant was also associated with Dupuytren's disease (OR = 2.31 [2.24, 2.39], p<1x10-300) as were a further two of the frozen shoulder associated variants. The Mendelian randomization results provided evidence that type 1 diabetes is a causal risk factor for frozen shoulder (OR = 1.03 [1.02-1.05], p = 3x10-6). There was no evidence that obesity was causally associated with frozen shoulder, suggesting that diabetes influences risk of the condition through glycemic rather than mechanical effects. We have identified genetic loci associated with frozen shoulder. There is a large overlap with Dupuytren's disease associated loci. Diabetes is a likely causal risk factor. Our results provide evidence of biological mechanisms involved in this common painful condition.