Information

Related Research Units

Tommy Fuss Center Research
Psychiatry Research
Knowles Lab Research

Research Overview

A biomarker is an objective sign that indicates the presence of disease arising from pathogenic biologic processes; this is distinct from a symptom, which is an indicator of illness perceived by a patient. Current methods of diagnosis and treatment for psychiatric disorders are entirely symptom-based, making for mediocre diagnostic reliability and treatment. Identifying biomarkers for psychiatric disorders will take us a step closer to developing a mechanistic understanding of their neural bases, allowing the development of the types of precise clinical diagnoses available in other medical specialties.

Dr. Knowles seeks to identify and validate blood-based biomarkers for psychiatric disorders. Promising leads for potential biomarkers in psychiatry exist, in particular genetic variation and also peripherally measured lipids and related inflammatory measures. These indices are objective, with well characterized biological underpinnings, and can be measured simply, noninvasively and inexpensively. However, they are not clinically translatable, indeed the identification of reliable biomarkers in psychiatry is lagging behind other medical specialties.

Current projects the Dr. Knowles is the PI of are focused on providing answers to the unknowns that contribute to this lag, including: validating peripheral lipids in brain by investigating the relationship between phosphatidylcholine and phosphatidylinositol measured in plasma via mass spectrometry and their major compounds choline and myo-inositol in the brain measured via mess spectroscopy; establishing the potential of blood-based lipids and inflammation as markers of imminent, dynamically-assessed, suicide risk; and relating specific aspects of bipolar disorder symptomatology to functional single-nucleotide variants (SNVs) and/or copy–number variants (CNVs) in voltage-gated calcium-channel gene networks in child-affected trios.

Research Background

Dr. Knowles specializes in statistical genetics. She was trained originally as a psychologist and worked briefly as a low-intensity cognitive behavioral therapist. During her post-doc she trained in family-based genetic analysis focussed on isolating the genetic underpinnings of risk for psychiatric disorders and also allied phenotypes (e.g. cognition, brain morphology). More recently Dr. Knowles has turned her attention to the identification and validation of blood-based biomarkers, especially lipids and inflammation, for affective disorders.

 

Publications

  1. Genetic Associations Among Inflammation, White Matter Architecture, and Extracellular Free Water. Hum Brain Mapp. 2025 Jan; 46(1):e70101. View Abstract
  2. Effects of gene dosage on cognitive ability: A function-based association study across brain and non-brain processes. Cell Genom. 2024 Dec 11; 4(12):100721. View Abstract
  3. Heritability, phenotypic, and genetic correlations across dimensional and categorical models of bipolar disorder in a family sample. J Affect Disord. 2025 Mar 01; 372:394-401. View Abstract
  4. Copy-number variants differ in frequency across genetic ancestry groups. HGG Adv. 2024 Oct 10; 5(4):100340. View Abstract
  5. Independent inheritance of cognition and bipolar disorder in a family sample. Am J Med Genet B Neuropsychiatr Genet. 2025 Jan; 198(1):e33001. View Abstract
  6. Admixture mapping of cognitive function in diverse Hispanic and Latino adults: Results from the Hispanic Community Health Study/Study of Latinos. Alzheimers Dement. 2024 Sep; 20(9):6070-6081. View Abstract
  7. Strong Genetic Overlaps Between Dimensional and Categorical Models of Bipolar Disorders in a Family Sample. medRxiv. 2024 Mar 26. View Abstract
  8. Cocktail-party listening and cognitive abilities show strong pleiotropy. Front Neurol. 2023; 14:1071766. View Abstract
  9. Impact of Copy Number Variants and Polygenic Risk Scores on Psychopathology in the UK Biobank. Biol Psychiatry. 2023 10 01; 94(7):591-600. View Abstract
  10. The Genetic contribution to solving the cocktail-party problem. iScience. 2022 Sep 16; 25(9):104997. View Abstract
  11. Similar Rates of Deleterious Copy Number Variants in Early-Onset Psychosis and Autism Spectrum Disorder. Am J Psychiatry. 2022 11 01; 179(11):853-861. View Abstract
  12. Specificity of Psychiatric Polygenic Risk Scores and Their Effects on Associated Risk Phenotypes. Biol Psychiatry Glob Open Sci. 2023 Jul; 3(3):519-529. View Abstract
  13. Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics. Neuropsychopharmacology. 2021 09; 46(10):1788-1801. View Abstract
  14. Genetic influences on externalizing psychopathology overlap with cognitive functioning and show developmental variation. Eur Psychiatry. 2021 03 31; 64(1):e29. View Abstract
  15. 1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans. Transl Psychiatry. 2021 03 22; 11(1):182. View Abstract
  16. Genetic Overlap Profiles of Cognitive Ability in Psychotic and Affective Illnesses: A Multisite Study of Multiplex Pedigrees. Biol Psychiatry. 2021 09 15; 90(6):373-384. View Abstract
  17. Effects of copy number variations on brain structure and risk for psychiatric illness: Large-scale studies from the ENIGMA working groups on CNVs. Hum Brain Mapp. 2022 01; 43(1):300-328. View Abstract
  18. Genetic Contributions to Multivariate Data-Driven Brain Networks Constructed via Source-Based Morphometry. Cereb Cortex. 2020 07 30; 30(9):4899-4913. View Abstract
  19. Minimal Relationship between Local Gyrification and General Cognitive Ability in Humans. Cereb Cortex. 2020 05 18; 30(6):3439-3450. View Abstract
  20. Strengths and Limitations of Harnessing Big Data to Understand the Genetics of Adoption and Mental Health. Biol Psychiatry. 2020 04 15; 87(8):e21-e22. View Abstract
  21. Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition. JAMA Psychiatry. 2020 04 01; 77(4):420-430. View Abstract
  22. Correction: Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia. Mol Psychiatry. 2020 Mar; 25(3):692-695. View Abstract
  23. Neurocognitive impairment in type 2 diabetes: evidence for shared genetic aetiology. Diabetologia. 2020 05; 63(5):977-986. View Abstract
  24. Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways. Am J Hum Genet. 2019 08 01; 105(2):334-350. View Abstract
  25. Evidence for genetic correlation between human cerebral white matter microstructure and inflammation. Hum Brain Mapp. 2019 10 01; 40(14):4180-4191. View Abstract
  26. Author Correction: Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function. Nat Commun. 2019 May 01; 10(1):2068. View Abstract
  27. Family-based analyses reveal novel genetic overlap between cytokine interleukin-8 and risk for suicide attempt. Brain Behav Immun. 2019 08; 80:292-299. View Abstract
  28. Cognitive impairment from early to middle adulthood in patients with affective and nonaffective psychotic disorders. Psychol Med. 2020 01; 50(1):48-57. View Abstract
  29. A QTL on chromosome 3q23 influences processing speed in humans. Genes Brain Behav. 2019 04; 18(4):e12530. View Abstract
  30. Clinical correlates of subsyndromal depression in African American individuals with psychosis: The relationship with positive symptoms and comorbid substance dependence. Schizophr Res. 2019 04; 206:333-346. View Abstract
  31. Genetic influence on cognitive development between childhood and adulthood. Mol Psychiatry. 2021 02; 26(2):656-665. View Abstract
  32. Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia. Mol Psychiatry. 2020 03; 25(3):584-602. View Abstract
  33. Disentangling the genetic overlap between cholesterol and suicide risk. Neuropsychopharmacology. 2018 12; 43(13):2556-2563. View Abstract
  34. Multi-Trait Analysis of GWAS and Biological Insights Into Cognition: A Response to Hill (2018). Twin Res Hum Genet. 2018 10; 21(5):394-397. View Abstract
  35. Rediscovering the value of families for psychiatric genetics research. Mol Psychiatry. 2019 04; 24(4):523-535. View Abstract
  36. Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence. Nat Genet. 2018 07; 50(7):912-919. View Abstract
  37. Assessment of Cognition and Personality as Potential Endophenotypes in the Western Australian Family Study of Schizophrenia. Schizophr Bull. 2018 06 06; 44(4):908-921. View Abstract
  38. Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function. Nat Commun. 2018 05 29; 9(1):2098. View Abstract
  39. Shared Genetic Factors Influence Head Motion During MRI and Body Mass Index. Cereb Cortex. 2017 12 01; 27(12):5539-5546. View Abstract
  40. Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets. Cell Rep. 2017 Nov 28; 21(9):2597-2613. View Abstract
  41. GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium. Mol Psychiatry. 2017 11; 22(11):1651-1652. View Abstract
  42. Deficits in visual working-memory capacity and general cognition in African Americans with psychosis. Schizophr Res. 2018 03; 193:100-106. View Abstract
  43. The Processing-Speed Impairment in Psychosis Is More Than Just Accelerated Aging. Schizophr Bull. 2017 07 01; 43(4):814-823. View Abstract
  44. Inferring pathobiology from structural MRI in schizophrenia and bipolar disorder: Modeling head motion and neuroanatomical specificity. Hum Brain Mapp. 2017 08; 38(8):3757-3770. View Abstract
  45. Epigenetic Age Acceleration Assessed with Human White-Matter Images. J Neurosci. 2017 05 03; 37(18):4735-4743. View Abstract
  46. Serum phosphatidylinositol as a biomarker for bipolar disorder liability. Bipolar Disord. 2017 03; 19(2):107-115. View Abstract
  47. The lipidome in major depressive disorder: Shared genetic influence for ether-phosphatidylcholines, a plasma-based phenotype related to inflammation, and disease risk. Eur Psychiatry. 2017 06; 43:44-50. View Abstract
  48. GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium. Mol Psychiatry. 2017 03; 22(3):336-345. View Abstract
  49. The genetic basis of the comorbidity between cannabis use and major depression. Addiction. 2017 01; 112(1):113-123. View Abstract
  50. Genome-wide significant loci for addiction and anxiety. Eur Psychiatry. 2016 08; 36:47-54. View Abstract
  51. A comprehensive tractography study of patients with bipolar disorder and their unaffected siblings. Hum Brain Mapp. 2016 10; 37(10):3474-85. View Abstract
  52. Genome-wide linkage on chromosome 10q26 for a dimensional scale of major depression. J Affect Disord. 2016 Feb; 191:123-31. View Abstract
  53. Recurrent major depression and right hippocampal volume: A bivariate linkage and association study. Hum Brain Mapp. 2016 Jan; 37(1):191-202. View Abstract
  54. Genome-wide significant linkage of schizophrenia-related neuroanatomical trait to 12q24. Am J Med Genet B Neuropsychiatr Genet. 2015 Dec; 168(8):678-86. View Abstract
  55. Genome-wide autozygosity is associated with lower general cognitive ability. Mol Psychiatry. 2016 06; 21(6):837-43. View Abstract
  56. Genetics of cognitive control: Implications for Nimh's research domain criteria initiative. Am J Med Genet B Neuropsychiatr Genet. 2016 Jan; 171B(1):111-20. View Abstract
  57. Independent evidence for an association between general cognitive ability and a genetic locus for educational attainment. Am J Med Genet B Neuropsychiatr Genet. 2015 Jul; 168B(5):363-73. View Abstract
  58. Brain structure-function associations in multi-generational families genetically enriched for bipolar disorder. Brain. 2015 Jul; 138(Pt 7):2087-102. View Abstract
  59. The puzzle of processing speed, memory, and executive function impairments in schizophrenia: fitting the pieces together. Biol Psychiatry. 2015 Dec 01; 78(11):786-93. View Abstract
  60. Genome-Wide Analyses of Working-Memory Ability: A Review. Curr Behav Neurosci Rep. 2014 Dec; 1(4):224-233. View Abstract
  61. Pleiotropic locus for emotion recognition and amygdala volume identified using univariate and bivariate linkage. Am J Psychiatry. 2015 Feb 01; 172(2):190-9. View Abstract
  62. Shared genetic factors influence amygdala volumes and risk for alcoholism. Neuropsychopharmacology. 2015 Jan; 40(2):412-20. View Abstract
  63. Discovering schizophrenia endophenotypes in randomly ascertained pedigrees. Biol Psychiatry. 2015 Jan 01; 77(1):75-83. View Abstract
  64. Influence of age, sex and genetic factors on the human brain. Brain Imaging Behav. 2014 Jun; 8(2):143-52. View Abstract
  65. Ventral anterior cingulate connectivity distinguished nonpsychotic bipolar illness from psychotic bipolar disorder and schizophrenia. Schizophr Bull. 2015 Jan; 41(1):133-43. View Abstract
  66. Heritable changes in regional cortical thickness with age. Brain Imaging Behav. 2014 Jun; 8(2):208-16. View Abstract
  67. Common genetic variants and gene expression associated with white matter microstructure in the human brain. Neuroimage. 2014 Aug 15; 97:252-61. View Abstract
  68. Hospital characteristics affecting potentially avoidable emergency admissions: national ecological study. Health Serv Manage Res. 2013 Nov; 26(4):110-8. View Abstract
  69. Arguments for the sake of endophenotypes: examining common misconceptions about the use of endophenotypes in psychiatric genetics. Am J Med Genet B Neuropsychiatr Genet. 2014 Mar; 165B(2):122-30. View Abstract
  70. Molecular genetic evidence for overlap between general cognitive ability and risk for schizophrenia: a report from the Cognitive Genomics consorTium (COGENT). Mol Psychiatry. 2014 Feb; 19(2):168-74. View Abstract
  71. Shared genetic factors influence risk for bipolar disorder and alcohol use disorders. Eur Psychiatry. 2014 Jun; 29(5):282-7. View Abstract
  72. Genome-wide significant localization for working and spatial memory: Identifying genes for psychosis using models of cognition. Am J Med Genet B Neuropsychiatr Genet. 2014 Jan; 165B(1):84-95. View Abstract
  73. Genetic basis of neurocognitive decline and reduced white-matter integrity in normal human brain aging. Proc Natl Acad Sci U S A. 2013 Nov 19; 110(47):19006-11. View Abstract
  74. Reduced white matter integrity in sibling pairs discordant for bipolar disorder. Am J Psychiatry. 2013 Nov; 170(11):1317-25. View Abstract
  75. Identification of pleiotropic genetic effects on obesity and brain anatomy. Hum Hered. 2013; 75(2-4):136-43. View Abstract
  76. A system-wide approach to explaining variation in potentially avoidable emergency admissions: national ecological study. BMJ Qual Saf. 2014 Jan; 23(1):47-55. View Abstract
  77. Dedifferentiation and substitute strategy: deconstructing the processing-speed impairment in schizophrenia. Schizophr Res. 2012 Dec; 142(1-3):129-36. View Abstract

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