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Background Polygenic risk scores (PRS) estimate an individual’s germline genetic predisposition to a quantitative trait and/or risk of disease. Several PRS have been developed for cancer risk with the goal of improved risk screening. Here, we sought to establish whether PRS for cancer risk and other common traits may influence survival for patients with cancer. Methods We conducted a PRS survival analysis using 23,770 cancer patients of European ancestry from the Dana-Farber Cancer Institute Profile cohort. Results We identified an association between PRS for breast cancer risk and longer patient survival (HR = 0.89 (95% CI: 0.84–0.95), p  = 1.50 × 10 –4 , < 5% FDR), implying that individuals at high genetic risk had better outcomes. High PRS individuals were also significantly less likely to harbor somatic TP53 mutations, consistent with having less aggressive tumors. This association persisted when including tumor grade and became more protective when restricting to ER-negative tumors (HR = 0.78 (95% CI: 0.68–0.89), p  = 1.69 × 10 –4 ). Potential confounders such as hormone receptor status, age, grade, stage, and ER-targeted therapy did not fully explain this association, nor was there statistical evidence of index event bias at individual variants. We did not observe significant associations between cancer risk and survival for other cancers, suggesting that this mechanism may be largely unique to breast cancer. However, we did observe associations between shorter survival and type 2 diabetes, bipolar, and pancreatitis PRS (1% FDR). Conclusions These findings suggest that higher germline risk may predispose individuals to less aggressive breast cancer tumors and provide novel insights into breast cancer development and prognosis.

Atopic dermatitis (AD) is a common inflammatory skin condition and prior genome-wide association studies (GWAS) have identified 71 associated loci. In the current study we conducted the largest AD GWAS to date (discovery N = 1,086,394, replication N = 3,604,027), combining previously reported cohorts with additional available data. We identified 81 loci (29 novel) in the European-only analysis (which all replicated in a separate European analysis) and 10 additional loci in the multi-ancestry analysis (3 novel). Eight variants from the multi-ancestry analysis replicated in at least one of the populations tested (European, Latino or African), while two may be specific to individuals of Japanese ancestry. AD loci showed enrichment for DNAse I hypersensitivity and eQTL associations in blood. At each locus we prioritised candidate genes by integrating multi-omic data. The implicated genes are predominantly in immune pathways of relevance to atopic inflammation and some offer drug repurposing opportunities. The genetic basis of atopic dermatitis is not fully understood. Here, the authors find 91 genetic loci associated with atopic dermatitis in a GWAS of >1million individuals, which highlight the importance of systemic immune regulation.

The ability to read is an important life skill and a major route to education. Dyslexia, characterized by difficulties with accurate/ fluent word reading, and poor spelling is influenced by genetic variation, with a twin study heritability estimate of 0.4–0.6. Until recently, genomic investigations were limited by modest sample size. We used a multivariate genome-wide association study (GWAS) method, MTAG, to leverage summary statistics from two independent GWAS efforts, boosting power for analyses of dyslexia; the GenLang meta-analysis of word reading ( N  = 27,180) and the 23andMe, Inc., study of dyslexia (N cases  = 51,800, N controls  = 1,087,070). We increased the effective sample size to 1,228,832 participants, representing the largest genetic study of reading-related phenotypes to date. Our analyses identified 80 independent genome-wide significant loci, including 36 regions which were not previously reported as significant. Of these 36 loci, 13 were novel regions with no prior association with dyslexia. We observed clear genetic correlations with cognitive and educational measures. Gene-set analyses revealed significant enrichment of dyslexia-associated genes in four neuronal biological process pathways, and findings were further supported by enrichment of neuronally expressed genes in the developing embryonic brain. Polygenic index analysis of our multivariate results predicted between 2.34–4.73% of variance in reading traits in an independent sample, the National Child Development Study cohort ( N  = 6410). Polygenic adaptation was examined using a large panel of ancient genomes spanning the last ~15 k years. We did not find evidence of selection, suggesting that dyslexia has not been subject to recent selection pressure in Europeans. By combining existing datasets to improve statistical power, these results provide novel insights into the biology of dyslexia.

Dyslexia is a learning difficulty with neurodevelopmental origins, manifesting as reduced accuracy and speed in reading and spelling. It is substantially heritable and frequently co-occurs with other neurodevelopmental conditions, particularly attention deficit-hyperactivity disorder (ADHD). Here, we investigate the genetic structure underlying dyslexia and a range of psychiatric traits using results from genome-wide association studies of dyslexia, ADHD, autism, anorexia nervosa, anxiety, bipolar disorder, major depressive disorder, obsessive compulsive disorder, schizophrenia, and Tourette syndrome. Genomic Structural Equation Modelling (GenomicSEM) showed heightened support for a model consisting of five correlated latent genomic factors described as: F1) compulsive disorders (including obsessive-compulsive disorder, anorexia nervosa, Tourette syndrome), F2) psychotic disorders (including bipolar disorder, schizophrenia), F3) internalising disorders (including anxiety disorder, major depressive disorder), F4) neurodevelopmental traits (including autism, ADHD), and F5) attention and learning difficulties (including ADHD, dyslexia). ADHD loaded more strongly on the attention and learning difficulties latent factor (F5) than on the neurodevelopmental traits latent factor (F4). The attention and learning difficulties latent factor (F5) was positively correlated with internalising disorders (.40), neurodevelopmental traits (.25) and psychotic disorders (.17) latent factors, and negatively correlated with the compulsive disorders (–.16) latent factor. These factor correlations are mirrored in genetic correlations observed between the attention and learning difficulties latent factor and other cognitive, psychological and wellbeing traits. We further investigated genetic variants underlying both dyslexia and ADHD, which implicated 49 loci (40 not previously found in GWAS of the individual traits) mapping to 174 genes (121 not found in GWAS of individual traits) as potential pleiotropic variants. Our study confirms the increased genetic relation between dyslexia and ADHD versus other psychiatric traits and uncovers novel pleiotropic variants affecting both traits. In future, analyses including additional co-occurring traits such as dyscalculia and dyspraxia will allow a clearer definition of the attention and learning difficulties latent factor, yielding further insights into factor structure and pleiotropic effects.

Neopterin is a pro-inflammatory molecule upregulated in several diseases; however, its role in pathophysiology is unclear and its genetic regulation is unexplored. We observed that neopterin levels increase during senescence ( P-value  = 1.88×10 -13 , beta  = 0.96) and positively correlate with age-related neurodegeneration and inflammation markers. The heritability estimation of neopterin variation was 35%. We then conducted a genome-wide association study on 999 Sardinians, identifying two signals in the GTP cyclohydrolase (GCH1) gene that were suggestively associated with neopterin levels. The first signal, led by rs140884539-C ( P-value  = 7.05×10 -08 , beta  = 0.59), was in strong linkage disequilibrium with variants associated with predisposition to rheumatoid arthritis, decrease in dopamine, increased levels of GCH1 transcript, dopamine metabolites, and galectin-3. The second signal, represented by rs12323905-T ( P-value  = 8.17×10 -08 , beta  = 0.30), colocalised with GCH1 splicing and Parkinson’s disease signals. Transcriptome analysis of 605 Sardinians showed that the Parkinson’s disease-predisposing variant was significantly associated with an increase in a shorter and inactive form of GCH1, whose presence is predicted to reduce the GCH1 decamer stability. The GCH1 homo-decamer regulates neopterin and tetrahydrobiopterin production, a cofactor required for the synthesis of dopamine and serotonin. Our data motivate experimental work to test whether modulating GCH1 expression or isoform ratio alters dopaminergic function in Parkinson’s disease models.

Background Early detection of Parkinson’s disease (PD), a neurodegenerative disease with central and peripheral nerve involvement, ensures timely treatment access. Microbes influence nervous system health and are altered in PD. Methods We examined gut and mouth microbiomes from recently diagnosed patients in a geographically diverse, matched case-control, shotgun metagenomics study. Results Here, we show greater alpha-diversity in 445 PD patients versus 221 controls. The microbial signature of PD includes overabundance of 16 OTUs, including Streptococcus mutans and Bifidobacterium dentium , and depletion of 28 OTUs. Machine learning models indicate that subspecies level oral microbiome abundances best distinguish PD with reasonably high accuracy (area under the curve: 0.758). Microbial networks are disrupted in cases, with reduced connectivity between short-chain fatty acid-producing bacteria the the gut. Importantly, microbiome diversity metrics are associated with non-motor autonomic symptom severity. Conclusions Our results provide evidence that predictive oral PD microbiome signatures could possibly be used as biomarkers for the early detection of PD, particularly when there is peripheral nervous system involvement. Stagaman et al. investigate the associations between early idiopathic Parkinson’s disease (PD) and the diversity and composition of both saliva and stool microbiomes in a large, geographically diverse US cohort. Abundances of saliva microbes, particularly Prevotella, Neisseria, and Streptococcus OTUs, best distinguish between controls and cases. Plain language summary Parkinson’s disease (PD) is a neurodegenerative disease that is characterized by both motor symptoms, such as tremors, and non-motor symptoms, such as constipation. Our aim was to determine whether there were differences in the number and types of microbes living in the saliva and intestines of people with and without PD. We saw significant differences in the microbial communities living in healthy controls compared to people with PD. Additionally, we found that the proportions of microbe types in saliva were the best at distinguishing between controls and cases, and identified the specific kinds of microbes that were driving this distinction. These results highlight the potential importance of the saliva microbiome in understanding the causes and symptomatology of PD.

Hyposmia (decreased smell function) is a common early symptom of Parkinson’s disease (PD). The shared genetic architecture between hyposmia and PD is unknown. We leveraged genome-wide association study (GWAS) results for self-assessment of ‘ability to smell’ and PD diagnosis to determine shared genetic architecture between the two traits. Linkage disequilibrium score (LDSC) regression found that the sense of smell negatively correlated at a genome-wide level with PD. Local Analysis of [co]Variant Association (LAVA) found negative correlations in four genetic loci near GBA1 , ANAPC4 , SNCA , and MAPT , indicating shared genetic liability only within a subset of prominent PD risk genes. Using Mendelian randomization, we found evidence for a strong causal relationship between PD and liability towards poorer sense of smell, but weaker evidence for the reverse direction. This work highlights the heritability of olfactory function and its relationship with PD heritability and provides further insight into the association between PD and hyposmia.

The study of hydrothermal vents is a young and fertile discipline. The latest findings, and the enticing prospects offered by new technology, came in for discussion at two meetings held late last year.

The study of hydrothermal vents is a young and fertile discipline. The latest findings, and the enticing prospects offered by new technology, came in for discussion at two meetings held late last year.