Psychiatric & Neurodevelopmental Genetics Unit Faculty

Current Research Projects

Brain Health Initiative (BHI) Project

A cutting-edge, new approach to protecting brain health, optimizing brain performance and fighting brain illness across the lifespan. It is a collaborative effort between the Massachusetts General Hospital and Brain Health Initiative, Inc., a 501(c)(3) based in Florida. The BHI was developed to build brain healthy communities through education, research and innovation in the Florida Suncoast region and beyond. In 2019, with donor support totaling $2.2 million, the BHI was established in the community of Lakewood Ranch (LWR) Florida and has since expanded to include communities in nearby Manatee and Sarasota counties.

The goal is ambitious: we aim to optimize brain health and performance and prevent brain disease throughout the lifespan. The BHI is organized to initially execute three primary components:

1. Build an observational longitudinal study that will prospectively follow a multigenerational cohort (via accelerated cohort designs) to identify risk and protective factors linked to brain health across the lifespan

2. Establish an “innovation accelerator” that will experimentally test interventions to promote brain health and prevent brain disease in the general population and among high-risk groups; these interventions will be tested where people live, learn, work and play

3. Promote a culture of brain health through community education and public engagement, founded on a collective impact approach, where community members are empowered to come together to solve a complex challenge like brain health.

The Stories Teeth Record of Newborn Growth (STRONG) Study

This study examines teeth as a potential biomarker of stress exposure in young children. Teeth are one of very few structures in the body that preserve a permanent history of prenatal growth and growth insults, which are determinants of neuropsychiatric disease. Primary tooth mineralization also begins during the second trimester of prenatal life and is completed postnatally during the first year of life, coinciding with some of the earliest periods of brain development. This study is examining how the Boston Marathon bombings and manhunt in 2013 affected mothers who were pregnant during that time, and how these events might be recorded in children’s teeth.

Recent Highlighted Publications

1. Teeth as potential new tools to measure early life adversity and subsequent mental health risk: An interdisciplinary review and conceptual model. Biological Psychiatry, 87(6), 502-513. PMID: 31858984.

2. Genetic susceptibility for major depressive disorder associates with trajectories of depressive symptoms across childhood and adolescence. Journal of Child Psychology and Psychiatry. PMID: 33125721.

3. NMeasures of adult psychological resilience following early-life adversity: How congruent are different measures? Psychological Medicine. PMID: 32406816.

4. A structured approach to evaluating life course hypotheses: Moving beyond analyses of exposed versus unexposed in the omics context. American Journal of Epidemiology. PMID: 33125040.

Recent Awards and Recognitions (2020)

• Erin C. Dunn: Research Mentor Award in Psychiatry, Massachusetts General Hospital
• Rebecca Mountain, postdoctoral research fellow in the Dunn Lab: NIH Pediatric Loan Repayment Program Award
• Alexandre Lussier, postdoctoral research fellow in the Dunn Lab: Early Career Investigator Oral Presentation Award for his presentation entitled “A prospective study of time-dependent exposures to adversity and DNA methylation in childhood and adolescence” at the World Congress of Psychiatric Genetics
• Daniella Gomez-Ochoa, student intern at the Dunn Lab: Received the Program for Research in Science and Engineering (PRISE) award, 10-week summer program that aims to build community and stimulate creativity among Harvard undergraduate researchers in the life, physical/natural, engineering and applied sciences.
• Daniella Gomez-Ochoa also Received the Mary Gordon Roberts Summer Thesis Award to support research that will contribute to her senior honors thesis. This award is given to Harvard students who are working within the Mind Brain Behavior Institute.

Lab website

Other Links
www.teethforscience.com
www.brainhealthinitiative.org

Current Research Projects

Statistical methods for trans-ethnic genetic studies

This project aims to develop novel statistical methods that can integrate multi-ethnic multi-omic data for improved trans-ethnic fine-mapping and polygenic prediction, and leverage global biobanks to elucidate the causal genetic architecture and benchmark the transferability of polygenic risk scores for a broad range of complex traits and diseases.

Integrative brain genomics
This project aims to integrate large-scale neuroimaging, genetic, transcriptomic and phenotypic data to dissect the genetic underpinnings of individual differences in brain morphology and function, and explore the genomic and brain bases of cognitive, behavioral and neuropsychiatric phenotypes.

Recent Highlighted Publications

1. Polygenic prediction via Bayesian regression and continuous shrinkage priors. Nature Communications, 2019; 10(1):1776.

2. Improving polygenic prediction in ancestrally diverse populations. medRxiv, 2021.

Lab website

Current Research Projects

Ex vivo models of psychiatric disease biology with human induced pluripotent stem cells (iPSCs):

We have reprogrammed fibroblasts from healthy human subjects as well as subjects with schizophrenia and bipolar disorder to generate iPSCs. We have differentiated iPSCs to excitatory pyramidal neurons, cortical interneurons as well as three-dimensional cerebral organoids and spheroids to identify disease-specific differences in the iPSC-derived neurons. In addition, we are co-culturing iPSC-derived microglia with neurons as well as iPSC-derived brain microvascular endothelial cells to examine the interplay of inflammation, neurovasculature and synaptic biology. We are utilizing a number of techniques including transcriptomic and proteomic approaches as well as functional studies with multielectrode arrays, in order to discover the mechanistic underpinnings of disease biology.

Chemical-genetic approaches to synaptic plasticity and human cognition:

We are studying the role of Arc/Arg3.1 in synaptic plasticity in human iPSC-derived neurons. We are using gene-editing of Arc with CRISPR to assess the effect of Arc downregulation and overexpression as well as specific mutations on synaptic biology. In addition, we are undertaking structure-activity relationship (SAR) studies with a number of small molecules to identify chemical moieties that are present in small molecules that increase Arc. We will use the SAR studies to synthesize a new set of analogs in order to develop new compounds that are optimized for enhancing Arc activity in human neurons, with an eye towards develop novel pro-cognitive therapeutic leads.   

Recent Highlighted Publications

1. Transcriptome analysis and functional characterization of cerebral organoids in bipolar disorder. Genome Med. 2020 Apr 19;12(1):34. doi: 10.1186/s13073-020-00733-6

2. Synaptic deficits in iPSC-derived cortical interneurons in schizophrenia are mediated by NLGN2 and rescued by N-acetylcysteine. Transl Psychiatry. 2019 Nov 28;9(1):321. doi: 10.1038/s41398-019-0660-x

3. Lysine Deacetylation by HDAC6 Regulates the Kinase Activity of AKT in Human Neural Progenitor Cells. ACS Chem Biol. 2017 Aug 18;12(8):2139-2148. doi: 10.1021/acschembio.6b01014.

Lab Website

Recent Highlighted Publications

Dr. Koenen writes for Psychology Today. Read more.

Koenen, Karestan C., et al. Treating Survivors of Childhood Abuse and Interpersonal Trauma: STAIR Narrative Therapy. Second edition ed., The Guilford Press, 2020.

Ng LC, Stevenson A, Kalapurakkel SS, Hanlon C, Seedat S, Harerimana B, Chiliza B, Koenen KC. National and regional prevalence of posttraumatic stress disorder in sub- Saharan Africa: A systematic review and meta-analysis. PLoS Med. 2020; 17: e1003090. PMC7228043.

Current Research Projects

Cross disorder analysis of major psychiatric disorders

The long-term goal of this project is to understand the shared genetic bases of psychiatric disorders to improve prevention, diagnosis and treatment of these serious illnesses. Recent successes of large-scale genomics studies have verified extensive sharing of common variant risk across major psychiatric disorders at a genome-wide level. Nevertheless, little is known of which and how certain genetic loci carry risk effects transcending traditional diagnostic boundaries. We are currently conducting systematic identification and functional characterization of genetic effects shared among eleven neuropsychiatric disorders using genome-wide SNP data on over 1 million individuals

Pain, mental health, and suicide

The long-term goal of this project is to understand the common underlying biological mechanisms between chronic pain, mental health conditions and suicide. Suicide is a serious public health threat, representing the second leading cause of death among children and adolescents in the USA. There are well-established risk factors of suicide including childhood adversity, socioeconomic disadvantages, physical disorders and the presence of mental illness. However, predicting suicide risk even among the high-risk group remains challenging mainly due to our limited understanding of etiology and the associated biomarkers. We are leveraging the latest advances in psychiatric genetics and machine learning to decipher the complex and temporal interplay of suicidal risk factors, physical pain and mental health conditions.

Recent Highlighted Publications

1. Investigating shared genetic basis across Tourette Syndrome and comorbid neurodevelopmental disorders along the impulsivity-compulsivity spectrum. ​Biological Psychiatry 2021; Online Published on Jan/5/2021.

2. Pleiotropy and cross-disorder genetics among psychiatric disorders. Biological Psychiatry 2020; Online Published Oct/9/2020. 

3. Genome wide meta-analysis identifies genomic relationships, novel loci, and pleiotropic mechanisms across eight psychiatric disorders.
Cell 2019; 179(7):1469-1482.

Lab Website

Current Research Projects

Dr. Neale is deeply committed to advancing psychiatric genetics as an active member of the Psychiatric Genomics Consortium (PGC) steering committee and analysis committee. He has served as a statistical advisor to analysts in other PGC working groups including addictions, autism, cross-disorder, TS/OCD and schizophrenia groups. These efforts underscore his commitment to understanding the genetic influences on psychiatric illness and how to translate those into insights into the biological basis of these diseases. He is currently co-chair the International Common Disease Alliance Maps Workgroup and have worked with many different international consortia, including the International Inflammatory Bowel Disease Genetics Consortium, GiANT and the Global Lipids Genomics Consortium.

The Neale lab has developed and disseminated some of the most widely used statistical approaches in genomics including LD Score regression enabling widespread evaluation of genetic correlation across complex traits. More recently, the Neale lab is developing Hail, a cloud-native software platform for scaling up genetic analyses, which we used to generate and QC the latest version of the gnomAD callset as well as conduct GWAS on ~10,000 traits in the UK Biobank sample which we released freely and publicly.

Recent Highlighted Publications

1. A framework allowing for improved inclusion of admixed individuals in large-scale association.” Nature Genetics. 2021 Jan 18. doi: 10.1038/s41588-020-00766-y. Online ahead of print. PMID: 33462486

2. Genome Aggregation Database Consortium, Neale BM, Daly MJ, MacArthur DG. “The mutational constraint spectrum quantified from variation in 141,456 humans.” Nature. 2020 May;581(7809):434-443. doi: 10.1038/s41586-020-2308-7. Epub 2020 May 27.PMID: 32461654

3. Exome sequencing in amyotrophic lateral sclerosis implicates a novel gene, DNAJC7, encoding a heat-shock protein.” Nature Neurosci2019 Dec;22(12):1966-1974. doi: 10.1038/s41593-019-0530-0. Epub 2019 Nov 25. PubMed PMID: 31768050; PubMed Central PMCID: PMC6919277.

4. Exome sequencing in schizophrenia-affected parent-offspring trios reveals risk conferred by protein-coding de novo mutations.” Nature Neuroscience.2020 Feb;23(2):185-193. doi: 10.1038/s41593-019-0564-3. Epub 2020 Jan 13. PubMed PMID: 31932770; PubMed Central PMCID: PMC7007385. (*Senior Author)

Recent Awards and Recognitions (2020)

• Early-Career Award, American Society of Human Genetics. This award recognizes the contributions of genetics and genomic scientists in their first 10 years as an independent invitesigator
• Major Grant (2020-2025). 1/4 Powering Genetic Discovery for Severe Mental Illness in Latin American and African Ancestries. NIH/NIMH 1U01MH125047-01. Multi PI ($3,225,210)

Lab Website

Current Research Projects

The FinnGen biobank study

FinnGen aims to collect and analyze genetic and lifelong health data from 500 000 Finnish residents representing almost 10% of the population. The study was launched in 2017 and has by the end of 2020 collected over 440 000 participants. The extensive longitudinal health data and the unique population structure of Finland provides the FinnGen study exeptional opportunities for gene variant discovery, analyses over diagnostic boundaries and disease trajectories. The FinnGen study is a global, private public partnership research project representing one of the largest studies of this type. Project aims to improve human health through genetic research, and ultimately identify new therapeutic targets and diagnostics for treating numerous diseases.

The SUPER-psychosis study

The Finnish SUPER study on genetic mechanisms of psychotic disorders is a part of the international Stanley Global Neuropsychiatric Genomics Initiative. The objective of the study is to better understand the genetic and biological background of psychotic disorders in order to provide more accurate information for the development of new therapeutic interventions. During years 2016-2018 over 10 500 psychosis patients interviewed, and their DNA and cell samples were collected. All samples have been GWAS genotyped and exome or whole genome sequenced. Due to the unique population structure of Finland the study provides exceptional opportunities for rare and low frequency gene variant identification.

Recent Highlighted Publications

Polygenic burden has broader impact on health, cognition, and socioeconomic outcomes than most rare and high-risk copy number variants.

Saarentaus EC, Havulinna AS, Mars N, Ahola-Olli A, Kiiskinen TTJ, Partanen J, Ruotsalainen S, Kurki M, Urpa LM, Chen L, Perola M, Salomaa V, Veijola J, Männikkö M, Hall IM, Pietiläinen O, Kaprio J, Ripatti S, Daly M, Palotie A. Mol Psychiatry. 2021 Feb 1. doi: 10.1038/s41380-021-01026-z. Online ahead of print. PMID: 33526825

Contribution of rare and common variants to intellectual disability in a sub-isolate of Northern Finland.

Kurki MI, Saarentaus E, Pietiläinen O, Gormley P, Lal D, Kerminen S, Torniainen-Holm M, Hämäläinen E, Rahikkala E, Keski-Filppula R, Rauhala M, Korpi-Heikkilä S, Komulainen-Ebrahim J, Helander H, Vieira P, Männikkö M, Peltonen M, Havulinna AS, Salomaa V, Pirinen M, Suvisaari J, Moilanen JS, Körkkö J, Kuismin O, Daly MJ, Palotie A. Nat Commun. 2019 Jan 24;10(1):410. doi: 10.1038/s41467-018-08262-y.PMID: 30679432 

Common Variant Burden Contributes to the Familial Aggregation of Migraine in 1,589 Families.

Gormley P, Kurki MI, Hiekkala ME, Veerapen K, Häppölä P, Mitchell AA, Lal D, Palta P, Surakka I, Kaunisto MA, Hämäläinen E, Vepsäläinen S, Havanka H, Harno H, Ilmavirta M, Nissilä M, Säkö E, Sumelahti ML, Liukkonen J, Sillanpää M, Metsähonkala L, Koskinen S, Lehtimäki T, Raitakari O, Männikkö M, Ran C, Belin AC, Jousilahti P, Anttila V, Salomaa V, Artto V, Färkkilä M; 23andMe Research Team; International Headache Genetics Consortium (IHGC), Runz H, Daly MJ, Neale BM, Ripatti S, Kallela M, Wessman M, Palotie A. Neuron. 2018 Sep 5;99(5):1098. doi: 10.1016/j.neuron.2018.08.029.PMID: 30189203 

Current Research Projects

We are applying models of synaptic pruning using patient-derived microglia, neurons and astrocytes to enable high-throughput screening of modulators of neurodevelopment and neurodegeneration.

We are applying electronic health records at scale to develop clinical decision support tools that integrate clinical and genomic data for psychiatric prescribing, and to estimate risk of suicide and other adverse outcomes.

Recent Highlighted Publications

1. Predicting change in diagnosis from major depression to bipolar disorder after antidepressant initiation. 2021 Jan;46(2):455-461. doi: 10.1038/s41386-020-00838-x. Epub 2020 Sep 14.

2. Laboratory Findings Associated With Severe Illness and Mortality Among Hospitalized Individuals With Coronavirus Disease 2019 in Eastern Massachusetts. JAMA Netw Open. 2020 Oct 1;3(10):e2023934. doi: 10.1001/jamanetworkopen.2020.23934

3. Increased synapse elimination by microglia in schizophrenia patient-derived models of synaptic pruning. Nat Neurosci. 2019 Mar;22(3):374-385. doi: 10.1038/s41593-018-0334-7. Epub 2019 Feb 4.

Recent Awards and Recognitions (2020)

• The lab is supported by multiple NIH and foundation grants

Lab website

Current Research Projects

How are neural stem cell activation-quiescence decisions physiologically regulated?

The decision to stay quiescent or generate a neuron is tightly regulated by environmental signals sensed directly by neural stem cells or niche components such as interneurons, endothelial cells and mature dentate granule neurons. Understanding the cell-autonomous and non-cell autonomous mechanisms by which the activation of neural stem cells and progenitors is regulated will inform how adult hippocampal neurogenesis functions as an adaptive encoding mechanism. We are probing the role of novel molecular factors in modulating neural stem cell activation-quiescence and symmetric/asymmetric division decisions and their regulation by specific stimuli such as stress. Targeting these factors may enable maintenance of the neural stem cell reservoir while stimulating adult hippocampal neurogenesis. Example: Vicidomini et al, Neuron 2020, Guo et al, manuscript in review.

What are the mechanisms underlying lineage homeostasis and experience dependent integration of adult-born neurons?

The functional integration of adult-born dentate granule neurons is tightly regulated so as to calibrate levels of neurogenesis commensurate with environmental demands. We are interested in how the activity and inputs onto mature dentate granule neurons influences neural stem cell activation and integration of young adult-born neurons into the circuit. By identifying the mechanisms underlying lineage homeostasis and neuronal competition, we may be able to leverage them to rejuvenate the dentate gyrus with stage-specific expansion of populations of adult-born neurons to enhance encoding and memory functions in adulthood, aging and in Alzheimer's disease. Example: McAvoy et al, Neuron 2016

How do properties and connectivity of dentate granule cells causally relate to their encoding and memory functions?

The physiological properties and connectivity of adult-born dentate granule neurons change with their maturation. Computational models have ascribed specific functions for adult-born neurons at different stages of maturation in combination with different circuit elements (interneurons, mossy cells) in mediating these functions. However, empirical and mechanistic evidence are lacking. By identifying genes encoding properties or connectivity with specific circuit elements, we have begun to address these questions using cellular imaging, physiology and behavior. In addition, we are developing strategies to probe stage-specific functions of these genes. Importantly, we will harness these factors (genetically and with small molecules) to assess the impact of discretely reengineering DG-CA3 connectivity to modulate pattern separation-completion balance in adulthood, ageing and in Alzheimer's disease. Example: Guo et al, Nature Medicine 2018, Miller and Sahay, Nature Neuroscience 2019

How do DG-CA3 computations influence cortical and subcortical circuits subserving memory and mood? 

Essential to understanding how adult hippocampal neurogenesis impacts memory processing, we need to interrogate how adult-born neurons influence neural activity in different hippocampal subregions. Although it is intuitive that the hippocampus-based processing of the environment dictates the way we respond to our environment, how encoding operations performed by adult-born neurons affect activity of prefrontal cortex, amygdala, hypothalamus to govern adaptive behavioral responses is poorly understood. Example: Raam et al Nature Communications 2017, Besnard et al, Nature Neuroscience 2019, Goode, Tanaka et al, Neuron 2020, Besnard et al, Cell Reports 2020, Besnard and Sahay BBR 2020

Recent Highlighted Publications

1. An Integrated Index: Engrams, Place cells, and Hippocampal Memory. Neuron(August 6, 2020) 

2. Communication, Cross Talk, and Signal Integration in the Adult Hippocampal Neurogenic (Jan 22, 2020)

3. Functions of Adult-born neurons in Hippocampal Memory Interference and Indexing. Nature Neuroscience, Focus Issue on Learning and Memory, (September, 2019)

4. Dorsolateral septum somatostatin interneurons gate mobility to calibrate context-specific behavioral fear responses Nature Neuroscience(Feb 04, 2019)

Lab Website

Current Research Projects

Integrating common and rare variation to discover genes for Tourette Syndrome (TS)

We are using genome-wide SNP array, whole exome sequencing and whole genome sequencing data from individuals with TS and their parents to identify rare, high impact gene variants that contribute to the development of this childhood-onset disease. We then plan to examine whether specific combinations of rare and common TS susceptibility gene variants may help to explain clinical markers of disease severity, with the long-term goals of predicting individuals at highest risk for severe, persistent disease and targeting new disease pathways for treatment.

Large-scale collaborative genetic and epigenetic studies of Tourette Syndrome (TS)

Through collaboration with all major Tourette Syndrome genetic research consortia, we will bring together ~12,000 individuals with TS and 50,000 ancestry-matched controls for genome-wide association and copy number variant analyses to identify definitive TS risk genes. We will then integrate these results with functional epigenomic and transcriptomic data from specific cell-types and tissues in the brain across human development, as well as imaging genetic data that can help to identify when and where in the brain TS risk genes cause disease.

Recent Highlighted Publications

1. Synaptic processes and immune-related pathways implicated in Tourette syndrome, Translational Psychiatry 2021

2. Identifying subtypes of trichotillomania (hair pulling disorder) and excoriation (skin picking) disorder using mixture modeling in a multicenter sample, J Psychiatric Research, 2020.

Recent Awards and Recognitions (2020)

• Elected Fellow to the Biological Sciences Section of the American Association for the Advancement of Science (AAAS)
• Member, Psychiatric Genomics Consortium (PGC) Coordinating Committee (2019)
• Co-Chair, PGC Tourette Syndrome/OCD Work Group

Lab website