twin studies of brain structure

Twin Studies of Brain Structure and Cognition in Schizophrenia

Authors Acknowledgments

  • Corresponding Author: Bianca Besteher, Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany.

  • Co-authors: Paolo Brambilla, Igor Nenadić - (Department affiliations: Milan and Marburg universities)

Article Information

  • Journal: Neuroscience and Biobehavioral Reviews 109 (2020)

  • Keywords: Cognition, Executive function, Magnetic resonance imaging (MRI), Morphometry, Schizophrenia, Twin studies

  • Received Date: August 26, 2019

  • Revised Date: December 9, 2019

  • Accepted Date: December 12, 2019

Abstract

  • Twin studies have significantly contributed to understanding the heritability of schizophrenia, indicating evidence of a genetic component.

  • Recent applications include investigating intermediate phenotypes and biomarkers in schizophrenia.

  • The review focuses on brain structure (T1 morphometry) and cognition using twin studies, highlighting genetic variance overlap and novel research models in the post-GWAS era.

1. Introduction

  • Schizophrenia is a severe psychiatric disorder associated with crippling individual suffering and functional impairments.

  • Clinical symptoms include:

    • Positive symptoms: delusions, hallucinations, thought disorder.

    • Negative symptoms: affective flattening, social withdrawal, poverty of speech.

  • Heritability Estimates:

    • Risk factors in first-degree relatives significantly increase likelihood of developing schizophrenia from ~1% to 20-45% in twins.

    • General estimate of heritability is about 80% (Braff and Tamminga, 2017).

  • Genome-wide association studies (GWAS) suggest a polygenic model for schizophrenia with risk genes of low and high effect sizes contributing to overall disease risk.

  • Neurodevelopmental Disturbances: Genetic risk variants may lead to observable clinical features or brain changes (Birnbaum and Weinberger, 2017).

  • Environmental factors also play a crucial role, indicating a balance between risk and protective factors (Radua et al., 2018).

  • Longitudinal twin studies aid in understanding evolving processes over time and integrating neurodevelopmental findings with dopamine system dysfunction (Howes et al., 2017).

  • Cognitive impairment is closely studied within schizophrenia, and neurocognitive testing reveals characteristic profiles of impairment affecting daily functioning (Green et al., 2014).

  • Certain cognitive domains, particularly executive function, are crucial for intervention and modifying outcomes in schizophrenia (Millan et al., 2016).

2. Methods

  • The literature review employed systematic searches on PubMed for twin studies comparing patients and their co-twins regarding brain structures and cognitive functions.

  • Inclusion criteria were:

    • Use of twin study design with schizophrenia patients

    • Measurement of brain structures or cognition

  • Initial Search Results: 239 articles:

    • Cognition (search string: "twin AND schizo* AND cognit*"): 152 initial results, narrowed down to 23.

    • Brain Structure (search string: "twin AND schizo* AND brain structur*"): 87 initial results, narrowed down to 22.

3. Twin Studies of Brain Structure in Schizophrenia

3.1. Early Twin Studies Using Discordant MZ Design with MRI

  • Early studies utilized monozygotic (MZ) twins discordant for schizophrenia to analyze brain structures (limited sample sizes).

  • Key Findings:

    • Volume reductions in affected twins: hippocampus (McNeil et al., 2000), caudate volumes (Bridle et al., 2002). Environmental mediators like obstetric complications focused on rather than genetic effects.

3.2. Advances in Structural Imaging Twin Studies

  • Increased sample sizes and the use of both monozygotic and dizygotic twins facilitated improved results and analyses.

  • Evidence for graded effects on brain volumes (e.g., thalamus, dorsolateral prefrontal cortex) indicating genetic liability.

  • Studies involved significant associations between diagnostic expressions and structural variations, moving toward complex modeling including genetic and epigenetic factors.

4. Summary of Studies on Brain Structure

  • Key Studies Documented:

    • De Zwarte et al., 2018: Smaller total volume in twins than controls.

    • Hedman et al., 2016: Genetic liability linked to progressive cortical thinning.

    • Cannon et al., 2005: Reduced gray matter in patients highlighting genetic contributions to decreased brain volume.
      (Detailed results can be referenced in Tables 1 and 2).

4. Twin Studies of Cognition in Schizophrenia

  • Cognition studies have evolved alongside brain imaging, often from smaller samples to advanced structural equation modeling.

  • Findings:

    • High heritability of cognitive functions, notably working memory and verbal fluency, demonstrates significant genetic overlays with schizophrenia liability.

    • The basic genetic architecture shows strong overlaps with deficit cognitive functions, validating the role of cognitive impairment as a facet of schizophrenia.

5. Discussion and Future Directions

  • Twin studies elucidate the genetic architecture of schizophrenia and its relationship with cognitive deficits and brain structure anomalies. Important ongoing research focuses on the complexities of shared genetic and environmental factors.

  • The review highlights the advantages of twin design studies over other familial studies for addressing genetic versus non-genetic contributions in schizophrenia pathology.

1. Introduction

  • Schizophrenia is a severe psychiatric disorder associated with crippling individual suffering and functional impairments.

  • Clinical symptoms include:

    • Positive symptoms: delusions, hallucinations, thought disorder.

    • Negative symptoms: affective flattening, social withdrawal, poverty of speech.

  • Twin studies have significantly contributed to understanding the heritability of schizophrenia, indicating evidence of a genetic component.

2. Literature Review: Biological/Genetic Factors

  • Heritability Estimates:

    • General estimate of heritability is about 80% (Braff and Tamminga, 2017).

    • Risk factors in first-degree relatives significantly increase the likelihood of developing schizophrenia from ∼1%\sim1\% to 20-45% in twins.

  • Polygenic Model: Genome-wide association studies (GWAS) suggest a polygenic model for schizophrenia with risk genes of low and high effect sizes contributing to overall disease risk.

  • Neurodevelopmental Disturbances: Genetic risk variants may lead to observable clinical features or brain changes (Birnbaum and Weinberger, 2017).

  • Brain Structure Anomalies:

    • Early studies using discordant monozygotic (MZ) twins for schizophrenia found volume reductions in affected twins, such as in the hippocampus (McNeil et al., 2000) and caudate volumes (Bridle et al., 2002).

    • Advances in imaging studies, with increased sample sizes of both monozygotic and dizygotic twins, provide evidence for graded effects on brain volumes (e.g., thalamus, dorsolateral prefrontal cortex) indicating genetic liability.

    • Studies show significant associations between diagnostic expressions and structural variations, pointing towards complex genetic and epigenetic factors.

    • Key Studies Documented:

      • De Zwarte et al., 2018: Reported smaller total brain volume in twins with schizophrenia than controls.

      • Hedman et al., 2016: Linked genetic liability to progressive cortical thinning.

      • Cannon et al., 2005: Identified reduced gray matter in patients, highlighting genetic contributions to decreased brain volume.

  • Cognitive Functions:

    • High heritability of cognitive functions, especially working memory and verbal fluency, shows significant genetic overlays with schizophrenia liability.

    • The basic genetic architecture demonstrates strong overlaps with deficit cognitive functions, validating cognitive impairment as a core aspect of schizophrenia.

3. Literature Review: Non-Genetic/Environmental Factors

  • Environmental factors play a crucial role, balancing risk and protective factors (Radua et al., 2018).

  • Early twin studies often focused on environmental mediators, such as obstetric complications, to explain brain structure differences in affected versus unaffected twins.

4. Treatment (External Research Needed)

  • The provided notes briefly mention that certain cognitive domains, particularly executive function, are crucial for intervention and modifying outcomes in schizophrenia (Millan et al., 2016). However, the notes do not detail specific treatment methods like medication or therapy for schizophrenia as a whole. You will need to find peer-reviewed studies for an effective treatment method.