Biology subjects

Lewis, C.

Publications and source records attributed to Lewis, C..

4 recordsLinked to original sources

bioRxiv2018

Transforming summary statistics from logistic regression to the liability scale: application to genetic and environmental risk scores

1. Abstract1.1. ObjectiveStratified medicine requires models of disease risk incorporating genetic and environmental factors. These may combine estimates from different studies and models must be easily updatable when new estimates become available. The logit scale is often used in genetic and environmental association studies however the liability scale is used for polygenic risk scores and measures of heritability, but combining parameters across studies requires a common scale for the estimates.\n\n1.2. MethodsWe present equations to approximate the relationship between univariate effect size estimates on the logit scale and the liability scale, allowing model parameters to be translated between scales.\n\n1.3. ResultsThese equations are used to build a risk score on the liability scale, using effect size estimates originally estimated on the logit scale. Such a score can then be used in a joint effects model to estimate the risk of disease, and this is demonstrated for schizophrenia using a polygenic risk score and environmental risk factors.\n\n1.4. ConclusionThis straightforward method allows conversion of model parameters between the logit and liability scales, and may be a key tool to integrate risk estimates into a comprehensive risk model, particularly for joint models with environmental and genetic risk factors.

epidemiology↗

bioRxiv2017

Human macrophages survive and adopt activated genotypes in living zebrafish

The inflammatory response, modulated both by tissue resident macrophages and recruited monocytes from peripheral blood, plays a critical role in human diseases such as cancer and neurodegenerative disorders. Here, we sought a model to interrogate human immune behavior in vivo. We determined that primary human monocytes and macrophages survive in zebrafish for up to two weeks. Flow cytometry revealed that human monocytes cultured at the physiological temperature of the zebrafish survive and differentiate comparable to cohorts cultured at human physiological temperature. Moreover, key genes that encode for proteins that play a role in tissue remodeling were also expressed. Human cells migrated within multiple tissues at speeds comparable to zebrafish macrophages. Analysis of gene expression of in vivo educated human macrophages confirmed expression of activated macrophage phenotypes. Here, human cells adopted phenotypes relevant to cancer progression, suggesting that we can define the real time immune modulation of human tumor cells during the establishment of a metastatic lesion in zebrafish.

developmental biology↗

bioRxiv2017

Gamma-Band Resonance Of Visual Cortex To Optogenetic Stimulation

Activated visual cortex typically engages in neuronal synchronization in the gamma-frequency band (30-90 Hz). Gamma-band synchronization is related to cognitive functioning, and its mechanisms have been extensively investigated, predominantly through in-vitro studies. To further elucidate its mechanisms in-vivo, we performed simultaneous optogenetic stimulation and electrophysiological recordings of visual cortical areas 17 and 21a in the anesthetized cat. Viral transfection with AAV1 or AAV9 under a CamKII promoter led to robust Channelrhodopsin-2 (ChR2) expression. Immunohistochemical analysis showed that all ChR2-expressing neurons were negative for Parvalbumin, consistent with predominant or exclusive expression in excitatory neurons. Optogenetic stimulation used primarily surface illumination directly above the transfected and recorded cells. Stimulation with constant light led to strong and sustained gamma-band synchronization with strength and bandwidth similar to visually induced gamma. Rhythmic stimulation with light-pulse trains or sinusoidal light modulation revealed strongest resonance for gamma-band frequencies. Gamma resonance was confirmed by optogenetic white-noise stimulation. White-noise stimulation allowed the quantification of the transfer function between the optogenetic stimulation and the local field potential response. This transfer function showed a dominant peak in the gamma band. Thus, we find that visual cortical circuits resonate most strongly to gamma-band components in their input. This resonance renders both the sensitivity to input, and the output of these circuits, selectively tuned to gamma.\n\nSignificance StatementActivated groups of cortical neurons often display rhythmic synchronization in the gamma-frequency band (30-90 Hz). Gamma-band synchronization is particularly well studied in visual cortex. We used optogenetics to control visual cortex neurons with light. Different optogenetic stimulation protocols, using constant light, rhythmically modulated light or white-noise modulated light, all demonstrated that the investigated circuits predominantly resonate to stimulation in the gamma band. The observed gamma-band resonance renders visual cortical circuits most sensitive to gamma-rhythmic synaptic inputs. This in turn renders their spike output and the ensuing interareal synchronization gamma rhythmic.\n\nThis work was supported by DFG (SPP 1665, FOR 1847, FR2557/5-1-CORNET to P.F.; EXC 1086, DI 1908/5-1, DI 1908/6-1 to I.D.), BMBF (01GQ1301 to I.D.), EU (HEALTH-F2-2008-200728-BrainSynch, FP7-604102-HBP, FP7-600730-Magnetrodes to P.F.; ERC Starting Grant OptoMotorPath to I.D.), a European Young Investigator Award to P.F., the FENS-Kavli Network of Excellence to I.D., National Institutes of Health (1U54MH091657-WU-Minn-Consortium-HCP to P.F.), the LOEWE program (NeFF to P.F. and I.D.). Present address of I.D.: Optophysiology, Bernstein Center and BrainLinks-BrainTools, University of Freiburg, Albertstrase 23, 79104 Freiburg, Germany.\n\nAuthor contributionsJ.N, C.M.L., T.W., P.F. designed research; J.N, C.M.L., T.W., P.J., I.D., P.F. performed experiments; J.N., C.M.L., T.W. analyzed data; J.N., P.F. wrote the paper.

neuroscience↗

bioRxiv2017

New insights on the pharmacogenomics of antidepressant response from the GENDEP and STAR*D studies: rare variant analysis and high-density imputation

Genome-wide association studies have generally failed to identify polymorphisms associated with antidepressant response. Possible reasons include limited coverage of genetic variants that this study tried to address by exome genotyping and dense imputation.\n\nA meta-analysis of Genome-Based Therapeutic Drugs for Depression (GENDEP) and Sequenced Treatment Alternatives to Relieve Depression (STAR*D) studies was performed at SNP, gene and pathway level. Coverage of genetic variants was increased compared to previous studies by adding exome genotypes to previously available genome-wide data and using the Haplotype Reference Consortium panel for imputation. Standard quality control was applied. Phenotypes were symptom improvement and remission after 12 weeks of antidepressant treatment. NEWMEDS consortium samples and Pharmacogenomic Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS) served for replication.\n\n7,062,950 SNPs were analysed in GENDEP (n=738) and STAR*D (n=1409). rs116692768 (p=1.80e-08, ITGA9 (integrin alpha 9)) and rs76191705 (p=2.59e-08, NRXN3 (neurexin 3)) were significantly associated with symptom improvement during citalopram/escitalopram treatment. At gene level, no consistent effect was found. At pathway level, the Gene Ontology terms GO:0005694 (chromosome) and GO:0044427 (chromosomal part) were associated with improvement (corrected p=0.007 and 0.045, respectively). The association between rs116692768 and symptom improvement was replicated in PGRN-AMPS (p=0.047), while rs76191705 was not. The two SNPs did not replicate in NEWMEDS.\n\nITGA9 codes for a membrane receptor for neurotrophins and NRXN3 is a transmembrane neuronal adhesion receptor involved in synaptic differentiation. Despite their meaningful biological rationale for being involved in antidepressant effect, no convincing replication was achieved. Further studies may help in clarifying their role.

genomics↗