Biology subjects

Smith, B.

Publications and source records attributed to Smith, B..

5 recordsLinked to original sources

bioRxiv2018

Genetic correlations between pain phenotypes and depression and neuroticism

Correlations between pain phenotypes and psychiatric traits such as depression and the personality trait of neuroticism are not fully understood. The purpose of this study was to identify whether eight pain phenotypes, depressive symptoms, major depressive disorders, and neuroticism are correlated for genetic reasons. Eight pain phenotypes were defined by a specific pain-related question in the UK Biobank questionnaire. First we generated genome-wide association summary statistics on each pain phenotype, and estimated the common SNP-based heritability of each trait using GCTA. We then estimated the genetic correlation of each pain phenotype with depressive symptoms, major depressive disorders and neuroticism using the the cross-trait linkage disequilibrium score regression (LDSC) method integrated in the LD Hub. Third, we used the LDSC software to calculate genetic correlations among pain phenotypes. All pain phenotypes were heritable, with pain all over the body showing the highest heritability (h2=0.31, standard error=0.072). All pain phenotypes, except hip pain and knee pain, had significant and positive genetic correlations with depressive symptoms, major depressive disorders and neuroticism. The largest genetic correlations occurred between neuroticism and stomach or abdominal pain (rg=0.70, P=2.4 x 10-9). In contrast, hip pain and knee pain showed weaker evidence of shared genetic architecture with these negative emotional traits. In addition, many pain phenotypes had positive and significant genetic correlations with each other indicating shared genetic mechanisms. Pain at a variety of body sites is heritable and genetically correlated with depression and neuroticism. This suggests that pain, neuroticism and depression share partially overlapping genetic risk factors.

genetics↗

bioRxiv2018

Enrichment of rare protein truncating variants in amyotrophic lateral sclerosis patients

To discover novel genetic risk factors underlying amyotrophic lateral sclerosis (ALS), we aggregated exomes from 3,864 cases and 7,839 ancestry matched controls. We observed a significant excess of ultra-rare and rare protein-truncating variants (PTV) among ALS cases, which was primarily concentrated in constrained genes; however, a significant enrichment in PTVs does persist in the remaining exome. Through gene level analyses, known ALS genes, SOD1, NEK1, and FUS, were the most strongly associated with disease status. We also observed suggestive statistical evidence for multiple novel genes including DNAJC7, which is a highly constrained gene and a member of the heat shock protein family (HSP40). HSP40 proteins, along with HSP70 proteins, facilitate protein homeostasis, such as folding of newly synthesized polypeptides, and clearance of degraded proteins. When these processes are not regulated, misfolding and accumulation of degraded proteins can occur leading to aberrant protein aggregation, one of the pathological hallmarks of neurodegeneration.

genomics↗

bioRxiv2017

A genome-wide association study finds novel genetic associations with broadly-defined headache in UK Biobank (N = 223,773)

Headache is the most common neurological symptom and a leading cause of years lived with disability. We sought to identify the genetic variants associated with a broadly-defined headache phenotype in 223,773 subjects from the UK Biobank cohort. We defined headache based on a specific question answered by the UK Biobank participants. We performed a genome-wide association study of headache as a single entity, using 74,461 cases and 149,312 controls. We identified 3,343 SNPs which reached the genome-wide significance level of P < 5 x 10-8. The SNPs were located in 28 loci, with the top SNP of rs11172113 in the LRP1 gene having a P value of 4.92 x 10-47. Of the 28 loci, 14 have previously been associated with migraine. Among 14 new loci, rs77804065 with a P value of 5.87 x 10-15 in the LINC02210-CRHR1 gene was the top SNP.\n\nPositive relationships (P < 0.001) between multiple brain tissues and genetic associations were identified through tissue expression analysis, whereas no vascular related tissues showed significant relationships. We identified several significant positive genetic correlations between headache and other psychological traits including neuroticism, depressive symptoms, insomnia, and major depressive disorder.\n\nOur results suggest that brain function is closely related to broadly-defined headache. In addition, we also found that many psychological traits have genetic correlations with headache.

genetics↗

bioRxiv2017

Genetic and environmental determinants of stressful life events and their overlap with depression and neuroticism

BackgroundStressful life events (SLEs) and neuroticism are risk factors for major depressive disorder (MDD). However, SLEs and neuroticism are heritable traits that are correlated with genetic risk for MDD. In the current study, we sought to investigate the genetic and environmental contributions to SLEs in a large family-based sample, and quantify any genetic overlap with MDD and neuroticism.\n\nMethodsA subset of Generation Scotland: the Scottish Family Health Study, consisting of 9618 individuals comprise the present study. We estimated the heritability of SLEs using pedigree-based and molecular genetic data. The environment was assessed by modelling familial, couple and sibling components. Using polygenic risk scores (PRS) and LD score regression we analysed the genetic overlap between MDD, neuroticism and SLEs.\n\nResultsPast 6-month life events were positively correlated with lifetime MDD status ({beta}=0.21, r2=1.1%, p=2.5 x 10-25) and neuroticism ({beta} =0.13, r2=1.9%, p=1.04 x 10-37). Common SNPs explained 8% of the variance in personal life events (those directly affecting the individual) (S.E.=0.03, p=9 x 10-4). A significant effect of couple environment accounted for 13% (S.E.=0.03, p=0.016) of variation in SLEs. PRS analyses found that individuals with higher PRS for MDD reported more SLEs ({beta} =0.05, r2=0.3%, p=3 x 10-5). LD score regression demonstrated genetic correlations between MDD and both SLEs (rG=0.33, S.E.=0.08) and neuroticism (rG=0.15, S.E.=0.07).\n\nConclusionsThese findings suggest that SLEs are partially heritable and this heritability is shared with risk for MDD and neuroticism. Further work should determine the causal direction and source of these associations.

genetics↗

bioRxiv2017

Correction of autoimmune IL2RA mutations in primary human T cells using non-viral genome targeting

Human T cells are central to physiological immune homeostasis, which protects us from pathogens without collateral autoimmune inflammation. They are also the main effectors in most current cancer immunotherapy strategies1. Several decades of work have aimed to genetically reprogram T cells for therapeutic purposes2-5, but as human T cells are resistant to most standard methods of large DNA insertion these approaches have relied on recombinant viral vectors, which do not target transgenes to specific genomic sites6, 7. In addition, the need for viral vectors has slowed down research and clinical use as their manufacturing and testing is lengthy and expensive. Genome editing brought the promise of specific and efficient insertion of large transgenes into target cells through homology-directed repair (HDR), but to date in human T cells this still requires viral transduction8, 9. Here, we developed a non-viral, CRISPR-Cas9 genome targeting system that permits the rapid and efficient insertion of individual or multiplexed large (>1 kilobase) DNA sequences at specific sites in the genomes of primary human T cells while preserving cell viability and function. We successfully tested the potential therapeutic use of this approach in two settings. First, we corrected a pathogenic IL2RA mutation in primary T cells from multiple family members with monogenic autoimmune disease and demonstrated enhanced signalling function. Second, we replaced the endogenous T cell receptor (TCR) locus with a new TCR redirecting T cells to a cancer antigen. The resulting TCR-engineered T cells specifically recognized the tumour antigen, with concomitant cytokine release and tumour cell killing. Taken together, these studies provide preclinical evidence that non-viral genome targeting will enable rapid and flexible experimental manipulation and therapeutic engineering of primary human immune cells.

genetics↗