Our lab focuses on understanding the genetic basis of brain conditions and illnesses. Our work has been covered in the popular press by Huffington Post, Stat the Emory Health Magazine, CNN, Medical Xpress (here and here).

Shared molecular mechanisms between psychiatric and neurodegenerative conditions

There is widespread pleiotropy among human traits and the high epidemiological comorbidity among the psychiatric and neurodegenerative diseases. In this project, we hypothesize that there are shared mechanisms among related brain traits. Specifically, we are focused on finding shared molecular contributors to brain conditions that underlie psychological traits, psychiatric conditions, and neurodegenerative illnesses.

  • A brain multi-omic approach to identify key molecular drivers of neuropsychiatric symptoms in Alzheimer’s dementia (NIH, R01 AG072120) - Approximately 65% of individuals with mild cognitive impairment (MCI), Alzheimer’s disease (AD), or AD related dementias (ADRD) experience neuropsychiatric symptoms (NPS). These debilitating symptoms include depression, anxiety, apathy, delusions, hallucinations, agitation, sleep disturbances and are associated with faster disease progression, greater functional impairment, higher caregiver burden, and earlier institutionalization. Current treatments for NPS in MCI/dementia have limited efficacy but high rates of adverse side effects, including higher mortality. In this project, we aim to gain better insight into the molecular mechanisms of NPS in MCI, dementia, or both to nominate therapeutic targets. We are using genomic investigation of well-described cohorts, exploration of brain mRNA and protein expression, and techniques integrating genetic and brain mRNA and protein expression findings to identify putative causal drivers of these debilitating symptoms.

  • Understanding the molecular mechanisms behind how psychological well-being and depression modify AD risk (NIH, R01 AG072120) - Psychological well-being (PWB) and depression are important factors that modify risk for Alzheimer’s disease (AD). Specifically, depression is associated with increased risk for AD while PWB with decreased risk for AD. Molecular mechanisms underlying these important associations, however, are not known. In this project, we collaborate with investigators of the Rush Memory and Aging Project to identify genomic, transcriptomic, and proteomic associations with PWB. These findings will be examined for their relationship to dementia and age-related brain pathologies to understand the role PWB may have on dementia risk.

Identifying putatively causal brain proteins in psychiatric and neurodegenerative conditions

Variation in brain protein expression likely underlies some of the reason for differences in why people develop different brain related traits. These projects aim to use results of large-scale genome-wide association studies (GWAS) and brain protein expression to identify genes that contribute to development of particular brain diseases.

  • Identifying novel brain proteins contributing to PTSD and alcohol use disorder (VA, I01 BX005686) - Post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) are among the most prevalent and debilitating psychiatric disorders in Veterans, and treatments for PTSD or AUD are ineffective in many patients. The overarching goal of this work is to identify brain proteins predisposing to PTSD, AUD, or both. These findings are likely to illuminate novel pathophysiology and potential drug targets. This work builds on insights into the complex genetic architecture of PTSD and AUD gained through large genome-wide association studies (GWAS), recent deep proteomic brain sequencing, and approaches that integrate information from GWAS with information about the genetic control of the human brain proteomes.

  • Elucidating molecular mechanisms of psychological well-being (VA, I01 BX003853) - Psychological well-being (PWB) is a multidimensional construct that encompasses positive emotion, life satisfaction, and sense of purpose and meaning in life, and is more than the absence of negative emotional states. Many prospective longitudinal studies have shown that PWB is associated with better mental and physical health. In this project we will investigate molecular mechanisms that underlie individual differences in PWB using human brain protein expression data.

Finding genetic and molecular the causes of Alzheimer’s Disease

Alzheimer’s Disease (AD) is a major health crisis and new treatment approaches are needed. Our work seeks to understand the role of sex in AD pathogenesis and identifying new AD genetic associations.

  • Integrative genomic, transcriptomic, and proteomic analyses to investigate sex-specific differences in Alzheimer’s disease (NIH R01 AG075827) - Women are affected by AD about twice as much as men. Why women are disproportionately affected by AD is not well understood. In this project, we hypothesize that there is an interaction between biological sex and brain protein expression that predisposes women to have a higher risk for AD. This hypothesis builds on our work investigating the genetic control of gene expression in the human brain but reframes the question by examining genes with evidence for differences in expression by sex.

  • A Proteogenomic Approach to Understanding Results of Genome-wide Association Studies of Alzheimer’s Disease (NIH P50 AG025688) - Recent genome wide association studies (GWAS) of AD have identified many regions associated with AD. This project explores the role of brain protein expression as a potential cause for those GWAS findings. It focuses on the role of brain protein abundance and the role of coding variants in AD.

  • Identifying New Genetic causes of Early-onset Alzheimer’s disease - Early-onset Alzheimer’s disease is a particularly aggressive form of the disease with higher heritability than typical late-onset AD and has several well-described genetic causes. This project uses next-generation sequencing to identify new genetic causes in families and individuals with this particularly aggressive form of AD.

  • A genetic study of a large pedigree with late-onset Alzheimer’s Disease - Late-onset Alzheimer’s Disease, the more common form of the disease, is due to the cumulative effect of 1,000s to 10,000s of genetic changes. However, there still appears to be families that transmit the illness as an autosomal dominant trait. The Emory GADRC has collected a number of very large families. We are using linkage and next-generation sequencing techniques to identify high-risk alleles in these families.

Transgenerational effects of maternal stressors: Investigating the role of infant gene expression

Several prospective, longitudinal, mother-child cohort studies have found that children exposed to maternal psychological stress, depression, or anxiety during the prenatal period have higher risk for behavioral and emotional problems later in life, including increased fearfulness, anxiety, and depression. This projects focuses on investigating molecular mechanisms underlying this association in collaboration with investigators at University of Cape Town in South Africa and at McLean Hospital. (NIH, U01 MH115484)

Accelerated aging and risk for Alzheimer’s disease in the Emory Healthy Brain and Emory Healthy Aging Studies

Accelerated aging occurs when a person’s biological age (as estimated by epigenetic DNA modification) is greater than their chronological age. In this project, we investigate if accelerated aging is associated with lower cognitive performance, higher rate of biomarker evidence for neurodegenerative disease, and higher genetic risk for AD.

Acknowledgements

We are grateful to the many research volunteers, their families, and researchers who make our work possible. We are indebted to our excellent collaborators. And we thank the financial support provided by the Veterans Administration, National Institutes of Health, Emory University, The To Remember Foundation, American Psychiatric Association, and the Brain and Behavior Foundation (formerly NARSAD).