Skip to main content
SpringerLink
Log in

Cognitive Phenotypes and Endophenotypes: Concepts and Criteria

  • Chapter
  • First Online:
Neurophenotypes

Part of the book series: Innovations in Cognitive Neuroscience ((Innovations Cogn.Neuroscience))

Abstract

Despite major advances in neuroscience, existing treatments for neuropsychiatric syndromes have only limited effectiveness. Because existing diagnoses rely on heterogeneous clusters of symptoms that are not closely associated with direct drug targets, discovery of new treatments almost always occurs by chance. Conventional diagnostic phenotypes are marked by significant heterogeneity and overlap, calling into question the biological validity of these diagnostic categories. In this chapter, the authors review the value of quantitative traits for unraveling complex disease and discuss phenotypes, endophenotypes, biomarkers, and cognitive phenotypes in particular. They then explore the necessary and sufficient criteria for viable cognitive phenotypes, including reproducibility and heritability. Next, they explore the utility of endophenotypes for genetic mapping studies, before moving on to discuss the specificity of cognitive phenotypes and their association with categorical disease phenotypes, their relevance to biological mechanisms, cognitive and neuroanatomic phenotypes in population samples, successful utilization of endophenotypes in the study of non-psychiatric complex traits, feasibility of animal models, multivariate phenotype approaches, and end with a description of the endophenotype ranking value (ERV). The authors conclude that defining new phenotypes at a neural systems level, with links to specific molecular targets, could yield dramatic advances in neuropsychiatric therapeutics. To achieve this, the current characterization of neuropsychiatric disorders must be dramatically revised by focusing on discrete, continuously distributed phenotypes, indexed by quantitative assays, that can help bridge molecular and behavioral constructs.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 99.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 129.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 129.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Almasy L (2003) Quantitative risk factors as indices of alcoholism susceptibility. Ann Med 35(5):337–343

    Google Scholar 

  • Anderson GG, Leaves NI, Bhattacharyya S et al (2002) Positive association to IgE levels and a physical map of the 13q14 atopy locus. Eur J Hum Genet 10(4):266–270

    Article  PubMed  Google Scholar 

  • Bearden CE, Freimer NB (2006) Endophenotypes for psychiatric disorders: ready for primetime? Trends Genet 22(6):306–313

    Article  PubMed  Google Scholar 

  • Berrettini WH (2000) Are schizophrenic and bipolar disorders related? A review of family and molecular studies. Biol Psychiatry 48(6):531–538

    Article  PubMed  Google Scholar 

  • Bilder RM (2008) Phenomics: building scaffolds for biological hypotheses in the post-genomic era. Biol Psychiatry 63(5):439–440

    Article  PubMed  PubMed Central  Google Scholar 

  • Bilder RM, Sabb FW, Cannon TD et al (2009a) Phenomics: the systematic study of phenotypes on a genome-wide scale. Neuroscience 164(1):30–42

    Article  PubMed  PubMed Central  Google Scholar 

  • Bilder RM, Sabb FW, Parker DS et al (2009b) Cognitive ontologies for neuropsychiatric phenomics research. Cogn Neuropsychiatry 14(4–5):419–450

    Article  PubMed  PubMed Central  Google Scholar 

  • Blangero J, Williams JT, Almasy L (2003) Novel family-based approaches to genetic risk in thrombosis. J Thromb Haemost 1(7):1391–1397

    Article  PubMed  Google Scholar 

  • Bohlken MM, Brouwer RM, Mandl RC et al (2016) Genetic variation in schizophrenia liability is shared with intellectual ability and brain structure. Schizophr Bull sbw034

    Google Scholar 

  • Burdick KE, Goldberg TE, Funke B et al (2007) DTNBP1 genotype influences cognitive decline in schizophrenia. Schizophr Res 89(1–3):169–172

    Article  PubMed  Google Scholar 

  • Burdick KE, Goldberg TE, Cornblatt BA et al (2011) The MATRICS consensus cognitive battery in patients with bipolar I disorder. Neuropsychopharmacology 36(8):1587–1592

    Article  PubMed  PubMed Central  Google Scholar 

  • Cannon TD, Huttunen MO, Lonnqvist J et al (2000) The inheritance of neuropsychological dysfunction in twins discordant for schizophrenia. Am J Hum Genet 67(2):369–382

    Article  PubMed  PubMed Central  Google Scholar 

  • Castellanos FX, Tannock R (2002) Neuroscience of attention-deficit/hyperactivity disorder: the search for endophenotypes. Nat Rev Neurosci 3(8):617–628

    Article  PubMed  Google Scholar 

  • Cho SC, Jung SW, Kim BN et al (2009) Temperament and character among Korean children and adolescents with anxiety disorders. Eur Child Adolesc Psychiatry 18(1):60–64

    Article  PubMed  Google Scholar 

  • Comuzzie AG, Hixson JE, Almasy L et al (1997) A major quantitative trait locus determining serum leptin levels and fat mass is located on human chromosome 2. Nat Genet 15(3):273–276

    Article  PubMed  Google Scholar 

  • Delawalla Z, Csernansky JG, Barch DM (2008) Prefrontal cortex function in nonpsychotic siblings of individuals with schizophrenia. Biol Psychiatry 63(5):490–497

    Article  PubMed  Google Scholar 

  • Donohoe G, Morris DW, Clarke S et al (2007) Variance in neurocognitive performance is associated with dysbindin-1 in schizophrenia: a preliminary study. Neuropsychologia 45(2):454–458

    Article  PubMed  Google Scholar 

  • Doyle AE, Faraone SV, Seidman LJ et al (2005) Are endophenotypes based on measures of executive functions useful for molecular genetic studies of ADHD? J Child Psychol Psychiatry 46(7):774–803. PMID: 15972070

    Google Scholar 

  • Egan MF, Hyde TM, Bonomo JB et al (2001) Relative risk of neurological signs in siblings of patients with schizophrenia. Am J Psychiatry 158(11):1827–1834

    Article  PubMed  Google Scholar 

  • Evans L, Akiskal HS, Keck PE Jr et al (2005) Familiality of temperament in bipolar disorder: support for a genetic spectrum. J Affect Disord 85(1–2):153–168

    Article  PubMed  Google Scholar 

  • Fallgatter AJ, Herrmann MJ, Hohoff C et al (2006) DTNBP1 (dysbindin) gene variants modulate prefrontal brain function in healthy individuals. Neuropsychopharmacology 31(9):2002–2010

    Article  PubMed  Google Scholar 

  • Freimer N, Sabatti C (2003) The human phenome project. Nat Genet 34(1):15–21

    Article  PubMed  Google Scholar 

  • Glahn DC, Therman S, Manninen M et al (2003) Spatial working memory as an endophenotype for schizophrenia. Biol Psychiatry 53(7):624–626

    Article  PubMed  Google Scholar 

  • Glahn DC, Curran JE, Winkler AM et al (2012) High dimensional endophenotype ranking in the search for major depression risk genes. Biol Psychiatry 71(1):6–14

    Article  PubMed  Google Scholar 

  • Goldberg TE, Hyde TM, Kleinman JE et al (1993) Course of schizophrenia: neuropsychological evidence for a static encephalopathy. Schizophr Bull 19(4):797–804

    Article  PubMed  Google Scholar 

  • Goldman-Rakic PS (1994) Working memory dysfunction in schizophrenia. J Neuropsychiatry Clin Neurosci 6(4):348–357

    Article  PubMed  Google Scholar 

  • Gottesman II, Shields J (1973) Genetic theorizing and schizophrenia. Br J Psychiatry 122(566):15–30

    Article  Google Scholar 

  • Gottesman II, Gould TD (2003) The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry 160(4):636–645

    Article  PubMed  Google Scholar 

  • Hallmayer JF, Kalaydjieva L, Badcock J et al (2005) Genetic evidence for a distinct subtype of schizophrenia characterized by pervasive cognitive deficit. Am J Hum Genet 77(3):468–476

    Article  PubMed  PubMed Central  Google Scholar 

  • Hasler G, Drevets WC, Manji HK et al (2004) Discovering endophenotypes for major depression. Neuropsychopharmacology 29(10):1765–1781

    Article  PubMed  Google Scholar 

  • Hasler G, Drevets WC, Gould TD et al (2006) Toward constructing an endophenotype strategy for bipolar disorders. Biol Psychiatry 60(2):93–105

    Article  PubMed  Google Scholar 

  • Hindorff LA, Sethupathy P, Junkins HA et al (2009) Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc Natl Acad Sci USA 106(23):9362–9367

    Article  PubMed  PubMed Central  Google Scholar 

  • Hyman SE (2007) Can neuroscience be integrated into the DSM-V? Nat Rev Neurosci 8(9):725–732

    Google Scholar 

  • Jentsch JD, Trantham-Davidson H, Jairl C et al (2009) Dysbindin modulates prefrontal cortical glutamatergic circuits and working memory function in mice. Neuropsychopharmacology 34(12):2601–2608

    Article  PubMed  PubMed Central  Google Scholar 

  • John B, Lewis KR (1966) Chromosome variability and geographic distribution in insects. Science 152(3723):711–721

    Article  PubMed  Google Scholar 

  • Karlsgodt KH, Bachman P, Winkler AM et al (2011a) Genetic influence on the working memory circuitry: behavior, structure, function and extensions to illness. Behav Brain Res 225(2):610–622

    Article  PubMed  PubMed Central  Google Scholar 

  • Karlsgodt KH, Robleto K, Trantham-Davidson H et al (2011b) Reduced dysbindin expression mediates N-methyl-d-aspartate receptor hypofunction and impaired working memory performance. Biol Psychiatry 69(1):28–34

    Article  PubMed  Google Scholar 

  • Karnik-Henry MS, Wang L, Barch DM et al (2012) Medial temporal lobe structure and cognition in individuals with schizophrenia and in their non-psychotic siblings. Schizophr Res 138(2–3):128–135

    Article  PubMed  PubMed Central  Google Scholar 

  • Kathiresan S, Voight BF, Purcell S et al (2009a) Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. Nat Genet 41(3):334–341

    Article  PubMed  Google Scholar 

  • Kathiresan S, Willer CJ, Peloso GM et al (2009b) Common variants at 30 loci contribute to polygenic dyslipidemia. Nat Genet 41(1):56–65. doi: 10.1038/ng.291

    Google Scholar 

  • Kendler KS, Walsh D (1998) The structure of psychosis: syndromes and dimensions. Arch Gen Psychiatry 55(6):508–509

    Article  PubMed  Google Scholar 

  • Kirov G, Ivanov D, Williams NM et al (2004) Strong evidence for association between the dystrobrevin binding protein 1 gene (DTNBP1) and schizophrenia in 488 parent-offspring trios from Bulgaria. Biol Psychiatry 55(10):971–975

    Article  PubMed  Google Scholar 

  • Kochunov P, Glahn DC, Lancaster JL et al (2010) Genetics of microstructure of cerebral white matter using diffusion tensor imaging. Neuroimage 53(3):1109–1116

    Article  PubMed  PubMed Central  Google Scholar 

  • Marlow AJ, Fisher SE, Francks C et al (2003) Use of multivariate linkage analysis for dissection of a complex cognitive trait. Am J Hum Gen 72(3):561–570

    Article  Google Scholar 

  • Matthysse S, Holzman PS (1987) Genetic latent structure models: implication for research on schizophrenia. Psychol Med 17(2):271–274

    Article  PubMed  Google Scholar 

  • Matthysse S, Holzman PS, Lange K (1986) The genetic transmission of schizophrenia: application of Mendelian latent structure analysis to eye tracking dysfunctions in schizophrenia and affective disorder. J Psychiatr Res 20(1):57–67

    Article  PubMed  Google Scholar 

  • McDonald C, Bullmore ET, Sham PC et al (2004) Association of genetic risks for schizophrenia and bipolar disorder with specific and generic brain structural endophenotypes. Arch Gen Psychiatry 61(10):974–984

    Article  PubMed  Google Scholar 

  • Olincy A, Ross RG, Harris JG et al (2000) The P50 auditory event-evoked potential in adult attention-deficit disorder: comparison with schizophrenia. Biol Psychiatry 47(11):969–977

    Article  PubMed  Google Scholar 

  • Palmer LJ, Burton PR, Faux JA et al (2000) Independent inheritance of serum immunoglobulin E concentrations and airway responsiveness. Am J Respir Crit Care Med 161(6):1836–1843

    Article  PubMed  Google Scholar 

  • Panizzon MS, Fennema-Notestine C, Eyler LT et al (2009) Distinct genetic influences on cortical surface area and cortical thickness. Cereb Cortex 19(11):2728–2735

    Article  PubMed  PubMed Central  Google Scholar 

  • Poldrack RA, Kittur A, Kalar D et al (2011) The cognitive atlas: toward a knowledge foundation for cognitive neuroscience. Front Neuroinform 5:17

    Article  PubMed  PubMed Central  Google Scholar 

  • Posthuma D, Luciano M, Geus EJ et al (2005) A genomewide scan for intelligence identifies quantitative trait loci on 2q and 6p. Am J Hum Genet 77(2):318–326

    Article  PubMed  PubMed Central  Google Scholar 

  • Rasetti R, Weinberger DR (2011) Intermediate phenotypes in psychiatric disorders. Curr Opin Genet Dev 21(3):340–348

    Article  PubMed  PubMed Central  Google Scholar 

  • Ritsner MS, Strous RD (2010) Neurocognitive deficits in schizophrenia are associated with alterations in blood levels of neurosteroids: a multiple regression analysis of findings from a double-blind, randomized, placebo-controlled, crossover trial with DHEA. J Psychiatr Res 44(2):75–80

    Article  PubMed  Google Scholar 

  • Rund BR (1998) A review of longitudinal studies of cognitive functions in schizophrenia patients. Schizophr Bull 24(3):425–435

    Article  PubMed  Google Scholar 

  • Sabb FW, Bearden CE, Glahn DC et al (2008) A collaborative knowledge base for cognitive phenomics. Mol Psychiatry 13(4):350–360

    Article  PubMed  PubMed Central  Google Scholar 

  • Sachdev PS, Thalamuthu A, Mather KA et al (2016) White matter hyperintensities are under strong genetic influence. Stroke 47(6):1422–1428

    Article  PubMed  Google Scholar 

  • Schwab SG, Knapp M, Mondabon S et al (2003) Support for association of schizophrenia with genetic variation in the 6p22.3 gene, dysbindin, in sib-pair families with linkage and in an additional sample of triad families. Am J Hum Genet 72(1):185–190

    Article  PubMed  Google Scholar 

  • Seidman LJ, Pepple JR, Faraone SV et al (1991) Wisconsin card sorting test performance over time in schizophrenia. Preliminary evidence from clinical follow-up and neuroleptic reduction studies. Schizophr Res 5(3):233–242

    Article  PubMed  Google Scholar 

  • Seidman LJ, Faraone SV, Goldstein JM et al (2002) Left hippocampal volume as a vulnerability indicator for schizophrenia: a magnetic resonance imaging morphometric study of nonpsychotic first-degree relatives. Arch Gen Psychiatry 59(9):839–849

    Article  PubMed  Google Scholar 

  • Shen KK, Dore V, Rose S et al (2016) Heritability and genetic correlation between the cerebral cortex and associated white matter connections. Hum Brain Mapp 37(6):2331–2347

    Article  PubMed  PubMed Central  Google Scholar 

  • Skuse DH (2001) Endophenotypes and child psychiatry. Br J Psychiatry 178(5):395–396

    Article  PubMed  Google Scholar 

  • Stein JL, Medland SE, Vasquez AA et al (2012) Identification of common variants associated with human hippocampal and intracranial volumes. Nat Genet 44(5):552–561

    Article  PubMed  PubMed Central  Google Scholar 

  • Straub RE, MacLean CJ, O’Neill FA et al (1995) A potential vulnerability locus for schizophrenia on chromosome 6p24-22: evidence for genetic heterogeneity. Nat Genet 11(3):287–293

    Article  PubMed  Google Scholar 

  • Straub RE, Jiang Y, MacLean CJ et al (2002) Genetic variation in the 6p22.3 gene DTNBP1, the human ortholog of the mouse dysbindin gene, is associated with schizophrenia. Am J Hum Genet 71(2):337–348

    Article  PubMed  PubMed Central  Google Scholar 

  • Suzuki K, Shikishima C, Ando J (2011) Genetic and environmental sex differences in mental rotation ability: a Japanese twin study. Twin Res Hum Genet 14(5):437–443

    Article  PubMed  Google Scholar 

  • Talbot K, Eidem WL, Tinsley CL et al (2004) Dysbindin-1 is reduced in intrinsic, glutamatergic terminals of the hippocampal formation in schizophrenia. J Clin Invest 113(9):1353–1363

    Article  PubMed  PubMed Central  Google Scholar 

  • Tang JX, Zhou J, Fan JB et al (2003) Family-based association study of DTNBP1 in 6p22.3 and schizophrenia. Mol Psychiatry 8(8):717–718

    Article  PubMed  Google Scholar 

  • Tang J, LeGros RP, Louneva N et al (2009) Dysbindin-1 in dorsolateral prefrontal cortex of schizophrenia cases is reduced in an isoform-specific manner unrelated to dysbindin-1 mRNA expression. Hum Mol Genet 18(20):3851–3863

    Article  PubMed  PubMed Central  Google Scholar 

  • Toulopoulou T, Rabe-Hesketh S, King H et al (2003) Episodic memory in schizophrenic patients and their relatives. Schizophr Res 63(3):261–271

    Article  PubMed  Google Scholar 

  • Tucker-Drob EM (2011) Global and domain-specific changes in cognition throughout adulthood. Dev Psychol 47(2):331–343

    Article  PubMed  PubMed Central  Google Scholar 

  • Tuulio-Henriksson A, Haukka J, Partonen T et al (2002) Heritability and number of quantitative trait loci of neurocognitive functions in families with schizophrenia. Am J Med Genet 114(5):483–490

    Article  PubMed  Google Scholar 

  • Vescovi PP, Coiro V, Volpi R et al (1992) Plasma beta-endorphin, but not met-enkephalin levels are abnormal in chronic alcoholics. Alcohol Alcohol 27(5):471–475

    PubMed  Google Scholar 

  • Waldman ID (2005) Statistical approaches to complex phenotypes: evaluating neuropsychological endophenotypes for attention-deficit/hyperactivity disorder. Biol Psychiatry 57(11):1347–1356. PMID: 15950007

    Google Scholar 

  • Weickert CS, Straub RE, McClintock BW et al (2004) Human dysbindin (DTNBP1) gene expression in normal brain and in schizophrenic prefrontal cortex and midbrain. Arch Gen Psychiatry 61(6):544–555

    Article  PubMed  Google Scholar 

  • Weickert CS, Rothmond DA, Hyde TM et al (2008) Reduced DTNBP1 (dysbindin-1) mRNA in the hippocampal formation of schizophrenia patients. Schizophr Res 98(1–3):105–110

    Article  PubMed  Google Scholar 

  • Whelan CD, Hibar DP, van Velzen LS et al (2016) Heritability and reliability of automatically segmented human hippocampal formation subregions. Neuroimage 128:125–137

    Article  PubMed  Google Scholar 

  • Williams JM, de Leeuw M, Black MD et al (1999) Factors associated with outcomes of persistent truncus arteriosus. J Am Coll Cardiol 34(2):545–553

    Article  PubMed  Google Scholar 

  • Yang Z, Zuo XN, McMahon KL et al (2016) Genetic and environmental contributions to functional connectivity architecture of the human brain. Cereb Cortex 26(5):2341–2352

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhang Y, Leaves NI, Anderson GG et al (2003) Positional cloning of a quantitative trait locus on chromosome 13q14 that influences immunoglobulin E levels and asthma. Nat Genet 34(2):181–186

    Article  PubMed  Google Scholar 

  • Zinkstok JR, de Wilde O, van Amelsvoort TA et al (2007) Association between the DTNBP1 gene and intelligence: a case-control study in young patients with schizophrenia and related disorders and unaffected siblings. Behav Brain Funct 3:19

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, USA

    Carrie E. Bearden, Katherine H. Karlsgodt & Robert Bilder

  2. Oxford Centre for Functional MRI of the Brain, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK

    Anderson Winkler

  3. Department of Psychology, University of California, Los Angeles, CA, USA

    Carrie E. Bearden & Katherine H. Karlsgodt

Authors
  1. Carrie E. Bearden
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anderson Winkler
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Katherine H. Karlsgodt
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Robert Bilder
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Carrie E. Bearden .

Editor information

Editors and Affiliations

  1. Communication science & Disorders/Behavioral Neuroscience , Emerson College; Boston University school of Medicine, BOSTON, Massachusetts, USA

    Vinoth Jagaroo

  2. Marine medical centre and Marine Medical Research, Chan School of Public Health , Tufts University School of medicine and Harvard TH, BOSTON, Massachusetts, USA

    Susan L. Santangelo

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer Science+Business Media LLC

About this chapter

Cite this chapter

Bearden, C.E., Winkler, A., Karlsgodt, K.H., Bilder, R. (2016). Cognitive Phenotypes and Endophenotypes: Concepts and Criteria. In: Jagaroo, V., Santangelo, S. (eds) Neurophenotypes. Innovations in Cognitive Neuroscience. Springer, Boston, MA. https://doi.org/10.1007/978-1-4614-3846-5_4

Download citation

Publish with us

Policies and ethics

Search

Navigation