Ashley R. Winslow

Identification of 15 genetic loci associated with risk of major depression in individuals of European descent

Despite strong evidence supporting the heritability of major depressive disorder (MDD), previous genome-wide studies were unable to identify risk loci among individuals of European descent. We used self-report data from 75,607 individuals reporting clinical diagnosis of depression and 231,747 individuals reporting no history of depression through 23andMe and carried out meta-analysis of these results with published MDD genome-wide association study results. We identified five independent variants from four regions associated with self-report of clinical diagnosis or treatment for depression. Loci with a P value <1.0 × 10−5 in the meta-analysis were further analyzed in a replication data set (45,773 cases and 106,354 controls) from 23andMe. A total of 17 independent SNPs from 15 regions reached genome-wide significance after joint analysis over all three data sets. Some of these loci were also implicated in genome-wide association studies of related psychiatric traits. These studies provide evidence for large-scale consumer genomic data as a powerful and efficient complement to data collected from traditional means of ascertainment for neuropsychiatric disease genomics.

BrainSeq: Neurogenomics to Drive Novel Target Discovery for Neuropsychiatric Disorders

We outline an ambitious project to characterize the genetic and epigenetic regulation of multiple facets of transcription in distinct brain regions across the human lifespan in samples of major neuropsychiatric disorders and controls. Initially focused on schizophrenia and mood disorders, the goal of this consortium is to elucidate the underlying molecular mechanisms of genetic associations with the goal of identifying novel therapeutic targets. The consortium currently consists of seven pharmaceutical companies and a not-for-profit medical research institution working as a precompetitive team to generate and analyze publicly available archival brain genomic data related to neuropsychiatric illness.

Identification of neurotoxic cytokines by profiling Alzheimer’s disease tissues and neuron culture viability screening

Alzheimer’s disease (AD) therapeutics based on the amyloid hypothesis have shown minimal efficacy in patients, suggesting that the activity of amyloid beta (Aβ) represents only one aspect of AD pathogenesis. Since neuroinflammation is thought to play an important role in AD, we hypothesized that cytokines may play a direct role in promoting neuronal death. Here, we profiled cytokine expression in a small cohort of human AD and control brain tissues. We identified AD-associated cytokines using partial least squares regression to correlate cytokine expression with quantified pathologic disease state and then used neuron cultures to test whether cytokines up-regulated in AD tissues could affect neuronal viability. This analysis identified cytokines that were associated with the pathological severity. Of the top correlates, only TNF-α reduced viability in neuron culture when applied alone. VEGF also reduced viability when applied together with Aβ, which was surprising because VEGF has been viewed as a neuro-protective protein. We found that this synthetic pro-death effect of VEGF in the context of Aβ was commensurate with VEGFR-dependent changes in multiple signaling pathways that govern cell fate. Our findings suggest that profiling of tissues combined with a culture-based screening approach can successfully identify new mechanisms driving neuronal death.

Transethnic genome-wide scan identifies novel Alzheimer's disease loci

Genetic loci for Alzheimers disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood.

Investigating the neuroimmunogenic architecture of schizophrenia

The role of the immune system in schizophrenia remains controversial despite numerous studies to date. Most studies have profiled expression of select genes or proteins in peripheral blood, but none have focused on the expression of canonical pathways that mediate overall immune response. The current study used a systematic genetic approach to investigate the role of the immune system in a large sample of post-mortem brain of patients with schizophrenia: RNA sequencing was performed to assess the differential expression of 561 immune genes and 20 immune pathways in dorsolateral prefrontal cortex (DLPFC) (144 schizophrenia and 196 control subjects) and hippocampus (83 schizophrenia and 187 control subjects). The effect of RNA quality on gene expression was found to be highly correlated with the effect of diagnosis even after adjustment for observable RNA quality parameters (i.e. RNA integrity), thus this confounding relationship was statistically controlled using principal components derived from the gene expression matrix. In DLPFC, 23 immune genes were found to be differentially expressed (false discovery rate <0.05), of which seven genes replicated in both directionality and at nominal significance (P<0.05) in an independent post-mortem DLPFC data set (182 schizophrenia and 212 control subjects), although notably at least five of these genes have prominent roles in pathways other than immune function and overall the effect sizes were minimal (fold change <1.1). In the hippocampus, no individual immune genes were identified to be differentially expressed, and in both DLPFC and hippocampus none of the individual immune pathways were relatively differentially expressed. Further, genomic schizophrenia risk profiles scores were not correlated with the expression of individual immune pathways or differentially expressed genes. Overall, past reports claiming a primary pathogenic role of the immune system intrinsic to the brain in schizophrenia could not be confirmed.

Self-report data as a tool for subtype identification in genetically-defined Parkinson’s Disease

Through a targeted recruitment 23andMe has collected DNA and patient-reported symptoms from more than 10,000 subjects reporting a physician-verified diagnosis of PD. This study evaluated the potential of self-report, web-based questionnaires to rapidly assess disease natural history and symptomology in genetically-defined PD populations. While average age-at-diagnosis was significantly lower in GBA mutation carriers compared to idiopathic PD, or iPD (idiopathic PD, defined as no GBA mutations and no LRRK2 G2019S mutation), there were no significant differences in symptoms. Conversely, LRRK2 G2019S carrier status significantly associated with reporting of milder daily symptoms of lightheadedness and several differences were observed at a false discovery rate < 0.1, including increased reporting of changes in walking as an initial symptom of disease, decreased reporting of lightheadedness upon standing, and milder symptoms related to daily functioning. The subclinical differences in symptoms reported by LRRK2 G2019S carriers suggest differences in underlying pathophysiology and/or disease progression in LRRK2 carriers compared to iPD. Importantly, we confirm previous findings in PD genetic subsets where disease characteristics were ascertained through clinical exam. Overall, these data support the effective use of self-report and genetic data to rapidly analyze information from a large disease population or difficult to identify genetic subgroups.