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  • Review Article
  • Published:

Psychiatric genetics: progress amid controversy

Nature Reviews Genetics volume 9, pages 527–540 (2008)Cite this article

Key Points

  • Most psychiatric disorders are highly heritable, yet few reproducible genetic risk factors have been identified by linkage analysis and candidate gene or genome-wide association studies.

  • Large genomic rearrangements have been found in a subset of patients with autism and schizophrenia, suggesting that recurrent and/or new mutations are involved in psychiatric disorders.

  • Several confirmed genetic risk factors of relevance to psychiatric disorders are with endophenotypes — that is, with quantitative phenotypes related to psychiatric disorders — rather than with diagnoses themselves.

  • The incorporation of environmental risk factors into analysis has helped to elucidate and identify some genetic risk factors. Longitudinal studies will be needed to identify gene-by-environment effects.

  • Psychiatric symptoms have a role in some Mendelian disorders that have known causes.

  • Unique families with rare syndromes have led to the identification of some common genetic risk variants.

  • The genetics of psychiatric disorders is complex and needs to be approached from several angles. It is therefore insufficient to focus only on linkage and association studies of clinical categories.

  • Increased sample size and meta-analyses of large existing studies might allow the identification of common risk variants of psychiatric disorders.

  • Future work will need to incorporate additional factors: alternative phenotypes; recurrent new mutations and rare, 'private' mutations that are not detectable by genome-wide association; the interaction of environment with genetic risk factors; and, by bioinformatic means, our growing knowledge of expression differences and biological pathways.

Abstract

Several psychiatric disorders — such as bipolar disorder, schizophrenia and autism — are highly heritable, yet identifying their genetic basis has been challenging, with most discoveries failing to be replicated. However, inroads have been made by the incorporation of intermediate traits (endophenotypes) and of environmental factors into genetic analyses, and through the identification of rare inherited variants and novel structural mutations. Current efforts aim to increase sample sizes by gathering larger samples for case–control studies or through meta-analyses of such studies. More attention on unique families, rare variants, and on incorporating environment and the emerging knowledge of biological function and pathways into genetic analysis is warranted.

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Figure 1: Psychiatric disorders overlap and might be extremes of personality traits.
Figure 2: Interacting genetic and environmental risk factors for depression.

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Acknowledgements

We thank J. Li, M. Boehnke, S. Sen and M. Meisler for comments on the manuscript. Funding of our work in psychiatric disorders is provided by the Nancy Pritzker Psychiatric Disorders Fund, the Heinz Prechter Bipolar Disorders fund, NARSAD, and the National Institutes of Health (MH070775, MH070793).

Author information

Authors and Affiliations

  1. Molecular and Behavioral Neuroscience Institute, University of Michigan, 5061 BSRB, 109 Zina Pitcher Place, Ann Arbor, 48109-2200, Michigan, USA

    Margit Burmeister

  2. Department of Psychiatry and Depression Center, University of Michigan, Rachel Upjohn Building, 4250 Plymouth Road

    Margit Burmeister, Melvin G. McInnis & Sebastian Zöllner

  3. Ann Arbor, 48109-5734, Michigan, USA

    Margit Burmeister, Melvin G. McInnis & Sebastian Zöllner

  4. Department of Human Genetics, 4909 Buhl Building, 1241 East Catherine Street, Ann Arbor, 48109-5618, Michigan, USA

    Margit Burmeister

  5. Department of Biostatistics, University of Michigan, M4140 SPH II, 109 South Observatory Sreet, Ann Arbor, 48019-2029, Michigan, USA

    Sebastian Zöllner

Authors
  1. Margit Burmeister
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  2. Melvin G. McInnis
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  3. Sebastian Zöllner
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Corresponding author

Correspondence to Margit Burmeister.

Supplementary information

Supplementary information S1 (table)

Psychiatric disorders: Symptoms, Diagnosis and Epidemiology (PDF 139 kb)

Supplementary information S2 (table)

Genetic associations with psychiatric disorders with selected references (PDF 296 kb)

Related links

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DATABASES

OMIM

Alzheimer disease

Angelman syndrome

attention deficit-hyperactivity disorder

autism

bipolar disorder

CHARGE syndrome

Huntington disease

Parkinson disease

schizophrenia

velocardiofacial syndrome

Brunner syndrome

Wolfram syndrome

FURTHER INFORMATION

Autism Genetic Research Exchange

Depression Center, University of Michigan

National Institute of Mental Health

National Institute of Mental Health (NIMH) genetics initiative study

Glossary

Heritability

The proportion of phenotypic variation that is explained by genetic variation.

Locus heterogeneity

When variation in different genes affects the same phenotype; it is also known as genetic heterogeneity. This should be contrasted with allelic heterogeneity, in which multiple variants in the same gene affect the same disease.

Penetrance

The probability of observing a specific phenotype for individuals carrying a particular genotype. If this probability is smaller than 1 for all genotypes of a variant then the variant has incomplete penetrance.

Odds ratio

A measure of effect size. Defined as the ratio of the odds of a disease being observed in one group of genotypes and the odds of a disease being observed in another group.

Linkage study

A family-based method to search for a chromosomal location of a gene by demonstrating co-segregation of the disease with genetic markers of known chromosomal location.

Association study

Genetic study looking for association between a disease and a genetic locus using either a case–control design or a family-based design.

Winner's curse

Upward bias of estimates of effect sizes on data sets that have previously passed through a screening procedure for a significant test statistic.

Candidate gene

A gene that might be involved in a particular disease. A biological candidate gene might be involved in the neurotransmitter system that is implicated by the psychoactive drugs used to treat a disorder (for example, serotonin system genes for depression), whereas a positional candidate gene is any gene that maps within a chromosomal region that is implicated by linkage.

Endophenotype

Heritable phenotype that is associated with a disease but that can be measured independently of disease status.

Phenomenology

Clinically descriptive, experiential and subjective dimensions of psychopathology.

Positional cloning

Method for identifying the location of a risk variant within a candidate region. Overlapping clones covering the candidate region are typed, and segments that co-segregate perfectly with the disease are identified. These clones are the most likely location of the risk variant.

Meta-analysis

Analysis combining the evidence of multiple data sets.

Non-parametric linkage analysis

Compares the observed segregation of marker alleles in affected and unaffected individuals with the expected segregation under the rules of Mendelian genetics. Deviation from the expected segregation is an indication of linkage.

Rank

Position of one result in a set of results ordered by their test statistic. If no true signal exists in the data, each rank is equally likely. Thus, studies can be combined by comparing the rank of genetic segments across studies.

Multiple testing

Usually, several genomic positions or phenotypes are tested for association or linkage in genetic mapping, and all of these tests have a probability of generating a false positive equal to α — a preset level of significance. Thus, the probability that at least one test generates a false positive is higher than α.

Haplotype

A combination of closely linked alleles that are inherited together as a unit. When the phase is unknown, then the haplotypes in an individual are unknown and need to be estimated.

Pseudo-autosomal

Regions on the sex chromosomes that are homologous between the X chromosome and the Y chromosome.

Type I error

Falsely rejecting the null hypothesis. In genetic studies this is usually equivalent to erroneously attributing a genetic effect when there is no genetic effect.

Case–control

Genetic study comparing genotype frequencies, allele frequencies or haplotype frequencies between a cohort carrying a disease and a control group. Significant differences between the groups might indicate LD between the screened genetic variant and a risk variant. The control group might be either screened to ensure it does not contain cases of the disease or it might be a random population sample.

Linkage disequilibrium

(LD). Preferential association of one allele of one locus with a particular allele of another locus. In the simplest case, a rare disease mutation might be in LD with alleles on nearby loci because the mutation arose only once, on a founder chromosome that carried specific alleles. Those loci close to the mutation have not been separated from the mutation during evolution. Therefore, alleles that were present in the founder chromosome are overrepresented in patients.

Allelic heterogeneity

When multiple variants in the same gene affect the same disease. This should be contrasted with genetic or locus heterogeneity, when variation in different genes affects the same phenotype.

Variance component analysis

Analysis in which the total variance is separated into the contribution from different components, such as genetic, environmental or interaction factors.

Functional magnetic resonance imaging

(fMRI). The subject is given a task (for example, recalling a sad event, remembering numbers or looking at pictures) and a measure (the blood oxygen-level dependent (BOLD) response) is taken. This measure is correlated with how much blood is used by nerve cells.

Longitudinal measurements

Repeated measurements of the same trait at multiple time points.

Rapid cycling bipolar disorder

A type of bipolar disorder in which the patient experiences four or more episodes of mania and/or depression per year.

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Burmeister, M., McInnis, M. & Zöllner, S. Psychiatric genetics: progress amid controversy. Nat Rev Genet 9, 527–540 (2008). https://doi.org/10.1038/nrg2381

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