Dr. Anderson is a Steering Committee member of the International Stroke Genetics Consortium, an organization made up of investigators from around the world devoted to using human genetics to explore the biology of stroke and derive new methods to prevent and treat cerebrovascular disease.  Dr. Anderson is involved in many large-scale genetics efforts in ischemic and hemorrhagic stroke, leveraging variants across the human genome in thousands of participants to refine our understanding of how cerebrovascular disease develops and evolves.

Informed by human genetic data, we develop NCL disease models that are then used in research studies aimed at identifying the earliest consequences of NCL gene mutations at the molecular, cellular and whole organism levels. These models are also used in research aimed at identifying NCL protein function, which is important for rational treatment strategies for these devastating and fatal disorders.

We use data from large, population-based birth cohorts in the United States and throughout the world to identify the genetic and environmental determinants of depression.

Genome-wide association studies for type 2 diabetes

Our group has taken research from bench to bedside by finding a dietary change that helps patients with a rare familial neuropathy. We discovered that the mutations causing HSAN1 induce a shift in the substrate preference from serine to alanine thereby forming a class of neurotoxic deoxysphingolipids. Based on the mechanism of this lipid generation, we hypothesized that L-serine supplementation would prove to be beneficial and were able to prove this in mice and humans with HSAN1.  In a first trial of this disorder (NCT01733407), patients on L-serine experienced significant improvement on a neuropathy scale and experienced less sharp pain compared to the placebo group.

Gene discovery for heart attack risk. The genetic basis for heart attack can be divided roughly into two categories: monogenic (a mutation in a single gene sufficient to lead to heart attack) and polygenic (the additive effect of multiple mutations contribute to risk for heart attack). Over the years, we have used a range of approaches to characterize DNA variation (genotyping, sequencing) and a variety of analysis techniques to associate genotype with phenotype.

Protective genes. We have compared the DNA sequence of individuals with and without heart attack to identify mutations the protect against heart attack (i.e., mutations which are over-represented in individuals free of disease when compared to individuals with disease).

Huntington’s disease is caused by a dominantly inherited CAG trinucleotide repeat expansion in the HTT gene that is both necessary and sufficient to generate clinical manifestations. The size of the expanded CAG repeat largely determines the rate of the pathogenic process that leads to neurological symptoms of HD. However, the size of the expansion does not perfectly predict individual age at onset of clinical disease, and unexplained variance show familial segregation, strongly suggesting the existence of genetic disease modifiers that interact with HTT-driven disease pathogenesis to alter the timing of clinical symptoms of HD. In order to identify human genetic factors capable of delaying or hastening age at onset of motor signs, Dr. Lee’s lab as part of the GeM-HD Consortium capitalized on the power of genome-wide association (GWA) analysis to compare naturally occurring single-nucleotide polymorphisms (SNPs) and age at onset unexplained by the CAG repeat size.

Huntingtin (HTT) is expressed ubiquitously, and is detected at all stages of development. The GC-rich HTT promoter sequence contains several consensus sequences. The main regulatory elements responsible for basal transcription were characterized by deletion assays, and several proteins were reported to bind to the HTT promoter region. Notably, the HTT gene is also highly regulated. For example, a substantial amount of variance in HTT mRNA levels in brains of genetically identical mice was reported, and HTT gene expression levels were altered by external stimuli. Importantly, knockout of one allele of the HTT gene leads to reduced mRNA levels in most tissues, suggesting that HTT mRNA level is not tightly regulated by a feedback loop. Considering the potential of HTT regulatory mechanisms as a target of HD, our lab is interested in understanding how (mutant) HTT expression is normally turned on and off.

Whole Genome Sequencing Data Analysis of Autism. My current research aims to develop a unified statistical framework and accompanying computational software to analyze whole genome sequencing data. In particular, I am interested in applying this framework to study the genetic etiology of autism spectrum disorders (ASD). Advances in next generation sequencing technology have provided a powerful, unbiased way to dissect the complex genetic architecture of ASD. Multiple, independent exome sequencing studies have demonstrated an etiologic role of de novo loss-of-function mutations, as well as the discovery of rare inherited risk mutations.  While encouraging, our understanding of the genetic landscape of ASD is still far from complete; Evaluation of rare genetic variants has focused on protein coding regions – overlooking more than 97% of the human DNA – as a result of limited power due to small sample sizes. Another crucial challenge is a lack of analytic strategies that can effectively harness the enormous number of non-coding variants. To address these challenges, I have secured access to genetic data on people with autism, specifically whole genome sequencing data of ASD (N=2,500) through collaborations with the faculty at the Broad Institute, UCLA, and Stanford University. Using this data, we will develop and test effective analytic strategies for the study of whole genome sequencing data.

Genetic analyses: unbiased search for Huntington’s disease modifiers  

Systems genetics: Huntington’s disease allelic series

Identify genes and pathways that are altered in rare human diseases. We have combined the MitoCarta protein inventory with human genetics and sequencing to discover over one dozen novel genes underlying Mendelian mitochondrial diseases.

We are developing an in-vitro high-throughput platform for drug screening and determination of dose-response curves of gene therapy strategies for monogenic vascular disorders using CRISPR CAS9, siRNA and lentiviral gene-editing in endothelial and smooth muscle cells.

We are actively recruiting MGH Heart Center patients to participate in the Cardiovascular Biorepository (CVBio) in collaboration with the Partners HealthCare Biobank, with the goal of identifying novel genetic factors contributing to life-threatening conditions such as dilated cardiomyopathy and arrhythmias.

We continue to enroll patients in genome-wide association studies and genome sequencing studies to identify the genes that influence stroke.

Gene Discovery. We are searching for genes underlying sleep patterns, sleep disorders and circadian rhythms (morning-lark/night owl behavior or chronotype), and performing functional studies to get biological insights into molecular mechanisms.

Severe, persistent TS may arise from different types and/or combinations of genetic risk. We hypothesize that TS disease severity and/or comorbidity could arise from a) high levels of polygenic risk alone, b) low polygenic risk plus a detrimental, large effect-size genetic variant (copy number variant (CNV), gene-disrupting coding mutation, deleterious chromosomal rearrangement), c) low-to-moderate polygenic risk plus non-genetic, “environmental” risk factors, or d) all of the above.  We take an agnostic approach to gene discovery and employ a wide range of gene discovery methods, including genome-wide association studies (GWAS), structural/copy number variation (CNV) analyses, and exome/genome sequencing to identify risk genes for TS and related neuropsychiatric disorders. These discoveries feed back into our computational models to develop a better understanding of how these cumulative risk factors contribute to disease.

Mitral valve prolapse (MVP) is a common cardiac valve disease that affects nearly 1 in 40 individuals. It can manifest as mitral regurgitation and is the leading indication for mitral valve surgery. Despite a clear heritable component, the genetic etiology leading to non-syndromic MVP has remained elusive. We used a large multigenerational family segregating non-syndromic MVP to identify a novel missense mutation in the DCHS1 gene, the human homologue of the Drosophila cell polarity gene dachsous (ds)

Genomewide analyses and cross-disorder analyses of autism, ADHD, bipolar disorder, depression, PTSD, schizophrenia, and others

Brain genomics: the neural and genetic architecture of mental illness

The New England Precision Medicine Consortium

To determine how fat mass and starvation survival is regulated, we use the genetic model system elegans, a barely visible roundworm. We use genome-wide functional genomic approaches to screen for fat regulatory pathways and starvation resistance. To date we have identified almost 500 genes that regulate fat metabolism and starvation resistance, 80% of which are conserved all the way to humans. As predicted, there is an incredible enrichment for 1) genes that cause both high fat and enhance starvation survival when knocked down or knocked out, and there is 2) genes that cause low fat mass and starvation sensitivity. Our major goal is now to decipher how this complex group of genes network to adapt to different nutrient levels to enable the most efficient metabolism and starvation defenses. Our hypothesis is that by understanding this gene network we will be able to identify how these genes contribute to regulation of metabolism in humans and contribute to obesity and diabetes.

We have been studying early events in insulin signaling in the liver to figure out several key questions: 1) how does insulin resistance start in the liver? 2) why does fatty liver develop in diabetes? And 3) are there therapeutic targets for diabetes in the liver that can help increase insulin sensitivity without promoting fatty liver disease? To study insulin signaling events, we model insulin signaling both in mammalian liver cells in culture and in mouse knockouts missing key signaling molecules in insulin signaling.

Characterization of structural variation contributing to human disease.

We have conducted a genetic screen using a Drosophila model of NF1 to look for dominant modifiers of the dNf1 pupal size defect. Initially we screened deficiencies on the 1st and 2nd chromosome that uncover 80% of annotated genes. We subsequently identified responsible genes in crosses with mutant alleles or by tissue-specific RNA interference (RNAi) knockdown.

Recent genome-wide association (GWAS) studies in HD patients point to a role for DNA repair genes in processes that determine the age of disease onset. We are testing the hypothesis that DNA repair genes also modify CAG repeat instability in patients and alter the rate of HD pathogenesis by acting at the level of the CAG mutation itself. We are deriving measures of repeat instability in patient tissues that we can use as quantitative molecular phenotypes in genetic association studies. We are also investigating the relationship between instability and pathogenesis in other repeat expansion diseases and the idea that common modifier genes may contribute to disease expression across many disorders.