- Email: [email protected]
Genetics of mood disorders
PATHOPHYSIOLOGICAL BASIS OF MOOD DISORDERS
Genetics of mood disorders Nick Craddock
Experienced clinicians have always known that bipolar disorder tends to run in families but this observation, although of enormous academic interest, has until recently had limited clinical utility. The situation is changing: major advances in molecular genetics over recent years have provided the tools needed to identify genes involved in conferring susceptibility to complex genetic disorders such as bipolar disorder and unipolar major depression. Findings are now emerging from the application of these methods that will both increase knowledge of the pathogenesis of major psychiatric disorders and facilitate the development of new clinical diagnostic approaches, including classifications that are both more valid and clinically useful. This contribution will focus on current molecular genetic approaches and recent findings. (Important genetic terms used in this contribution are listed in Figure 1.)
Classical genetic studies Several important features of the inheritance of mood disorders will be familiar to most clinicians: • mood disorders often aggregate in families • the mode of inheritance is complex and does not usually follow simple Mendelian patterns (e.g. autosomal dominant, recessive or sex-linked) • within families in which more than one member is affected by mood disorder there is frequently a spectrum of illness phenotype, which may include unipolar depression, bipolar disorder, alcoholism, suicide or psychosis. Although a large number of classical family and twin studies of mood disorder have been undertaken, it is only in the last 30–40 years that researchers have divided illness into bipolar and unipolar forms. Data from both the early1 and more recent family, twin and adoption studies are consistent in demonstrating the important role that genes play in susceptibility to mood disorders.2-4 Equally,
Nick Craddock MBChB MMedSci PhD FRCPsych was Professor of Molecular Psychiatry and Head of the University of Birmingham Department of Psychiatry and Division of Neuroscience until 2002, when he moved to his current position of Professor of Psychiatry at Cardiff University, UK. He studied mathematical sciences at Cambridge University followed by Medicine at Birmingham University, and trained in clinical psychiatry in Birmingham and psychiatric genetics in Cardiff and St Louis, USA. His research focus is the molecular genetic investigation of bipolar spectrum mood disorders and psychosis. He has a specific interest in using molecular genetics to refine the clinical phenotype. His clinical interests lie in the management of treatment-resistant bipolar spectrum disorders.
PSYCHIATRY 5:5
170
© 2006 Elsevier Ltd
PATHOPHYSIOLOGICAL BASIS OF MOOD DISORDERS
Lifetime risk (%) of affective disorder in relatives of either a bipolar proband or a unipolar depression proband
Important genetic terms Meaning
Phenotype
The observable characteristics; in medical genetics, often used interchangeably with the term ‘disorder’
Genotype
Genetic marker
Linkage study
Association study
70
Lifetime prevalence (%)
Term
The set of genes inherited by an individual; usually used in reference to the set of genes related to the phenotype of interest A known location in the DNA sequence at which there is variation between individuals; this can be used to track genes within the population or within families
Polymorphism
A position in the DNA sequence that varies commonly between individuals in the population – they are therefore useful as markers
Single Nucleotide Polymorphism (SNP; pronounced ‘snip’)
A polymorphism in which the variation is at one of the nucleotide bases
Linkage disequilibrium
When used in psychiatric genetics this usually refers to assocation between a variant of a genetic marker and disease – this implies close proximity of the marker to the disease gene
30 20 10 (Pop)
(Sib)
(MZ)
(Pop)
(Sib)
(MZ)
Unipolar disorder
Pop, population; Sib, sibling of a proband; MZ, monozygotic co-twin of a proband.
2
by estimates of heritability, typically in the region of 80–90% for bipolar disorder and 30–40% for major depression.
Mode of inheritance Having established that genes play a role in mood disorder, what sort of genetic model might we anticipate? In a small number of families it is possible that illness may be determined primarily by a single gene; however, for most mood disorder in the population it is likely that several, or many, genes are involved. The most plausible genetic models involve interaction and co-action between multiple genes together with environmental factors. It is probable that some genes confer risk to both bipolar and unipolar illness whilst others confer specific risk to one or other of the major forms of mood disorder.
Molecular genetic studies Linkage and association studies using DNA markers are at the cutting edge of modern psychiatric genetics. Linkage studies use families in which more than one member is affected by disease, whereas association studies use unrelated affected probands and appropriate comparison individuals. Conceptually, molecular genetic studies can be divided into positional and candidate gene approaches. In positional approaches, the chromosomal locations of susceptibility genes are determined, usually by linkage studies. This requires no knowledge of disease pathophysiology and can be considered a purely genetic approach. This has obvious attractions for the study of psychiatric illnesses where pathogenesis is poorly understood. In contrast, the candidate gene approach presupposes that the researcher has sufficient understanding of disease biology to be able to recognize genes that may be involved in bipolar disorder. These are then examined in linkage or association studies. In practice, both positional and candidate approaches are often combined in a positional candidate approach. To date, substantially more molecular genetic research has been
1
they show that factors other than straightforward genetics must also play a role, with the twin concordance data being the most important evidence for this. Figure 2 shows the approximate recurrence risk estimates for major affective disorder in various classes of relative of a proband with either bipolar disorder or unipolar depression. The estimates of lifetime risk are taken from studies conducted over the past 30 years that have used the modern concept of bipolar and unipolar disorders. (These figures are approximate and illustrative. There are wide variations between estimates in individual studies, particularly of unipolar depression, reflecting variations in clinical populations and methods. Note that individuals with a bipolar relative are also at a substantially increased risk of unipolar depression compared with a member of the general population.) The genetic contribution to bipolar disorder is greater than that for unipolar depression, as demonstrated
PSYCHIATRY 5:5
40
Bipolar disorder
A study in which genetic markers are used within samples of unrelated individuals and some form of controls to locate disease susceptibility genes An association study in which a large set of markers (of the order of 500,000) is studied, distributed systematically across all chromosomes
50
0
A study in which genetic markers are used within sets of families multiply affected by illness to locate disease susceptibility genes
Whole-genome association study
60
171
© 2006 Elsevier Ltd
PATHOPHYSIOLOGICAL BASIS OF MOOD DISORDERS
undertaken in bipolar disorder that in unipolar depression, reflecting the increased effort that has been focused on the phenotype under greater genetic influence.
systems that are influenced by medications used in clinical management of the disorders. Variants in several well-known genes have received substantial attention and, for some of these (the genes encoding the serotonin transporter and the enzymes monoamine oxidase A (MAOA) and catechol-o-methyl transferase (COMT)), at least one meta-analysis of studies has shown evidence for association. However, estimated effect sizes are all small and overall significances are modest. It should be noted that, in the face of the small expected genetic effect sizes (odd ratios (OR) in the expected range (OR < 2)), a sample size of 500–1000 is required to provide adequate power to replicate. Such sample sizes are only just becoming routinely used in genetic studies. Thus, it is likely to be some time before the issue is definitively settled as to whether and to what extent polymorphisms within these genes contribute to the risk of bipolar illness. The two best supported genes of interest to emerge from recent studies of bipolar disorder are DAOA and BDNF. D-amino acid oxidase activator DAOA(G72)/G30 locus – at least five independent datasets contribute evidence that variation at the DAOA/G30 locus on chromosome 13q influences susceptibility to bipolar disorder. This locus was implicated originally as being involved in susceptibility to schizophrenia. It was a novel locus, with a designation of G72, which was found by positional studies. The locus was renamed as D-amino acid oxidase activator, DAOA, because biological studies suggested that the gene product activated the enzyme D-amino acid oxidase (DAO). In addition to the positive bipolar findings, association has been replicated in additional schizophrenia samples. No pathologically relevant variant has yet been identified and the biological mechanism remains to be elucidated. Brain-Derived Neurotrophic factor (BDNF) – a functional candidate gene that has attracted a great deal of recent interest is BrainDerived Neurotrophic factor (BDNF), located on chromosome 11p13. BDNF plays an important role in promoting and modifying growth, development and survival of neuronal populations and, in the mature nervous system, is involved in activity-dependent neuronal plasticity. These processes are prominent in the synaptic plasticity hypothesis of mood disorder. There have been three positive reports using family-based association studies of Caucasian bipolar disorder samples of European-American origin and a common amino acid-altering single nucleotide polymorphism (SNP): two were based on adult bipolar samples and one was based on a small childhood onset sample. In our own Caucasian bipolar case-control sample (N=3062) we found no overall evidence of allele or genotype association. However, we found significant association with disease status in the subset of cases that had experienced rapid cycling (4 or more episodes per year) at some time, and a similar association on re-analysis of our previously reported family-based association sample. This suggests that variation at BDNF may not play a major role in influencing susceptibility to bipolar disorder as a whole but, rather, may be associated with susceptibility to a specific aspect of the clinical bipolar phenotype.
Bipolar disorder Linkage studies: after early difficulties in which apparently promising findings based on a search for major genes could not be replicated, the research field has moved forward using methodologies more appropriate for the study of complex genetic traits. At least 20 systematic genome screens have been conducted on a variety of sample sets, ranging from single large densely affected pedigrees in genetic isolates to samples comprising several hundred affected sib pairs. The pattern of findings is consistent with there being no single gene of major effect to explain the majority of cases of bipolar disorder and with that expected in the search for genes for a complex disorder: several broad chromosomal regions of interest have emerged; no finding replicates in all datasets; and for individual positive findings levels of statistical significance and estimated effect sizes are usually modest. The field has reached sufficient maturity that meta-analyses and combined analyses of genome scans have been undertaken. Figure 3 shows chromosomal regions that have been identified in at least one genome scan as showing evidence for linkage that is significant at the genome-wide level (a stringent level of statistical significance that takes account of testing markers across the whole genome). It should be noted that additional regions have been implicated by multiple studies showing evidence at a lower level of significance.5 Association studies: good candidate gene studies depend critically on the choice of good candidates – this inevitably depends on the current understanding of disease pathophysiology. Most of the earlier candidate gene studies focused on neuro-transmitter
Chromosome regions that have achieved genomewide significant linkage in linkage genome scans of mood disorders* Chromosomal region
Bipolar disorder
Unipolar depression
1q42
+
2p13
+
4p16
+
4q32
+
6q21-q25
+
8q24
+
12q22–q24
++
15q14
+
15q25–q26
Schizoaffective disorder, bipolar type
+ +
Unipolar disorder Linkage studies: family members of bipolar probands who themselves suffer with unipolar depression have been included in the broad phenotype in most studies of bipolar disorder. However, compared with bipolar disorder and schizophrenia, relatively few
+, one study; ++, two studies. *Several other chromosomal regions are implicated through multiple studies showing linkage signals at a lower level of signifiance.
3
PSYCHIATRY 5:5
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© 2006 Elsevier Ltd
PATHOPHYSIOLOGICAL BASIS OF MOOD DISORDERS
genome scans of unipolar disorder as the main phenotype have been conducted to date and there have been no meta-analyses undertaken. However, linkage signals significant at a genome-wide level have been reported (see Figure 3).
Management implications of identifying susceptibility genes The schematic diagram below shows the probable development of changes affecting clinical management. It may be possible to start better tailoring of existing treatments to patients’ individual needs in the near future. The development of effective new treatments and prophylactic interventions is likely to take many years.
Association studies: as with linkage studies, to date, less attention has been given to genetic association studies of unipolar disorder than has been the case for bipolar disorder or schizophrenia. There are no unambiguous positive findings but the literature is developing rapidly. Given the expected smaller effect sizes and the possibility of greater clinical heterogeneity in unipolar disorder compared with bipolar disorder and schizophrenia, it can be expected that larger samples are likely to be required both for detection and replication of susceptibility loci. Perhaps the most interesting finding to emerge to date is the report of interaction between a functional variant at the serotonin transporter gene and the occurrence of life events in early adulthood.6 There have been both positive and negative attempts at replication. It is widely assumed that gene–environment interactions and co-action will occur in mood disorder and this finding may prove to be the first such example, although robust replication is required.
Treatment implications Now
Future 4
Molecular genetics and the Kraepelinian dichotomy Traditionally, psychiatric research in general, and the search for predisposing genes in particular, has proceeded under the assumption that schizophrenia and mood disorder are separate disease entities with separate underlying aetiologies (and treatments) – the so-called ‘Kraepelinian dichotomy’. However, molecular genetic studies are challenging this view. Several chromosomal regions have been implicated by linkage studies of both bipolar disorder and schizophrenia. Of particular interest is a genome scan of schizoaffective disorder, bipolar type, which showed genome-wide significant linkage (Figure 3) and supports the existence of one or more genes that influence susceptibility to a ‘third psychosis’. Most convincingly, several recent reports implicate variation at the same loci as influencing susceptibility to both schizophrenia and bipolar disorder. For example, the best supported locus for bipolar disorder is DAOA, which was originally identified in studies of schizophrenia. Other genes for which there is evidence of association for both disorders include Disrupted In Schizophrenia 1 (DISC1), COMT and Neuregulin 1 (NRG1). Such findings provide strong evidence (which is consistent with family and twin data) that there are genetic loci that contribute susceptibility across the Kraepelinian divide to schizophrenia, bipolar disorder and schizoaffective disorders. This has important implications for classification of the major psychiatric disorders because an overlap has been demonstrated in the biological basis of disorders that, over the last one hundred years, have been assumed to be distinct entities. Molecular genetic findings allow a re-appraisal of psychiatric nosology as well as providing a path to understanding the pathophysiology that will facilitate development of improved treatments. Rather than classifying psychosis as a dichotomy, a more useful formulation may be to conceptualize a spectrum of clinical phenotype with susceptibility conferred by overlapping sets of genes.
studies of mood disorders. Replications of current findings in large, well-characterized samples are required to determine their robustness and generalizability. It will be necessary to undertake detailed phenotype–genotype studies across the mood–psychosis spectrum, as well as functional biological studies to determine how biological variation influences clinical phenotype. It can be expected that some current findings will prove to be false positives and there will be many more susceptibility or disease-modifying genes to be identified in future studies. New methodologies, including whole-genome association studies, can be expected to complement existing approaches to facilitate progress.
Clinical, psychosocial and ethical issues Identification of susceptibility and modifying genes for mood and psychotic disorders has the potential to radically change the practice of psychiatry, alter the perception of mental illness and greatly enhance the understanding and treatability of some of the common major illnesses that afflict populations around the world. One of the earliest clinical benefits is likely to be better recognition of clinically and biologically homogeneous groups, with a consequent improved ability to tailor existing treatments to the individual patient. The likely time course for other developments is shown in Figure 4. Some of the advances will be accompanied by important ethical and psychosocial issues, including availability of new technology, access to genetic information and the subtle shift from a simple doctor–patient relationship to a doctor–patient–family relationship. It will be essential that an informed and balanced approach is taken to address these so that major advances in scientific understanding can be translated into major advances in clinical care.
Conclusions A robust body of classical genetic data indicates the existence of susceptibility genes in mood disorders. The current positional and candidate molecular genetic studies are producing replicable
The future Positive findings are beginning to emerge from molecular genetic
PSYCHIATRY 5:5
• More precise tailoring of existing treatments to individual patient profiles • Greater use of medication for clinical dimensions rather than diagnoses • New treatments based on deeper understanding of pathogenesis and better models • Prophylactic interventions
173
© 2006 Elsevier Ltd
PATHOPHYSIOLOGICAL BASIS OF MOOD DISORDERS
results. The best supported genes for bipolar disorder are DAOA and BDNF, and for unipolar depression the gene encoding the serotonin transporter. Evidence is accumulating that challenges the traditional Kraepelinian dichotomy. It is likely that many susceptibility genes will be discovered and characterized in the next few years and this will greatly enhance our understanding of disease pathogenesis and psychiatric nosology. Consequently, this has the potential to lead to a revolution in clinical psychiatry which will benefit psychiatrists, patients and their families. It is also extremely important to recognize that there are a number of ethical issues that will accompany these developments, and these will need to be considered very carefully.
REFERENCES 1 Tsuang M T, Faraone S V. The genetics of mood disorders. Baltimore: Johns Hopkins University Press, 1990. 2 McGuffin P, Katz R. The genetics of depression and manic-depressive disorder. Br J Psychiatry 1989; 155: 294. 3 Craddock N, Jones I. The genetics of bipolar disorder. J Med Genet 1999; 36: 585–94. 4 Sullivan P F, Neale M C, Kendler K S. Genetic epidemiology of major depression: review and meta-analysis. Am J Psychiatry. 2000; 157: 1552–62. 5 Craddock N, O’Donovan M C, Owen M J. The genetics of schizophrenia and bipolar disorder: dissecting psychosis. J Med Genet 2005; 42: 288–99. 6 Caspi A, Sugden K, Moffitt T E et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 2003; 301: 386–9. FURTHER READING Bishop T, Sham P. Analysis of multifactorial disease. Human molecular genetics. London: BIOS Scientific Publishers Ltd, 2000. Craddock N, Forty L. The genetics of affective (mood) disorders. Eur J Hum Genet, forthcoming. Craddock N, Owen M J. The beginning of the end for the Kraepelinian dichotomy. Br J Psychiatry 2005; 186: 364–6. Jones I, Kent L, Paul M, Craddock N. Clinical implications of psychiatric genetics in the new millennium – nightmare or nirvana? Psych Bull 2001; 25: 129–31. McGuffin P, Owen M, Gottesman I I. Psychiatric genetics and genomics. Oxford: Oxford University Press, 2002. Nuffield Council on Bioethics. Mental disorders and genetics: the ethical context. London: Nuffield Council on Bioethics, 1998. Plomin R, DeFries J C, McClearn G E, McGuffin P. Behavioral genetics: a primer. 4th edition. New York: W H Freeman and Company, 2001.
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© 2006 Elsevier Ltd
Genetics of mood disorders Nick Craddock
Experienced clinicians have always known that bipolar disorder tends to run in families but this observation, although of enormous academic interest, has until recently had limited clinical utility. The situation is changing: major advances in molecular genetics over recent years have provided the tools needed to identify genes involved in conferring susceptibility to complex genetic disorders such as bipolar disorder and unipolar major depression. Findings are now emerging from the application of these methods that will both increase knowledge of the pathogenesis of major psychiatric disorders and facilitate the development of new clinical diagnostic approaches, including classifications that are both more valid and clinically useful. This contribution will focus on current molecular genetic approaches and recent findings. (Important genetic terms used in this contribution are listed in Figure 1.)
Classical genetic studies Several important features of the inheritance of mood disorders will be familiar to most clinicians: • mood disorders often aggregate in families • the mode of inheritance is complex and does not usually follow simple Mendelian patterns (e.g. autosomal dominant, recessive or sex-linked) • within families in which more than one member is affected by mood disorder there is frequently a spectrum of illness phenotype, which may include unipolar depression, bipolar disorder, alcoholism, suicide or psychosis. Although a large number of classical family and twin studies of mood disorder have been undertaken, it is only in the last 30–40 years that researchers have divided illness into bipolar and unipolar forms. Data from both the early1 and more recent family, twin and adoption studies are consistent in demonstrating the important role that genes play in susceptibility to mood disorders.2-4 Equally,
Nick Craddock MBChB MMedSci PhD FRCPsych was Professor of Molecular Psychiatry and Head of the University of Birmingham Department of Psychiatry and Division of Neuroscience until 2002, when he moved to his current position of Professor of Psychiatry at Cardiff University, UK. He studied mathematical sciences at Cambridge University followed by Medicine at Birmingham University, and trained in clinical psychiatry in Birmingham and psychiatric genetics in Cardiff and St Louis, USA. His research focus is the molecular genetic investigation of bipolar spectrum mood disorders and psychosis. He has a specific interest in using molecular genetics to refine the clinical phenotype. His clinical interests lie in the management of treatment-resistant bipolar spectrum disorders.
PSYCHIATRY 5:5
170
© 2006 Elsevier Ltd
PATHOPHYSIOLOGICAL BASIS OF MOOD DISORDERS
Lifetime risk (%) of affective disorder in relatives of either a bipolar proband or a unipolar depression proband
Important genetic terms Meaning
Phenotype
The observable characteristics; in medical genetics, often used interchangeably with the term ‘disorder’
Genotype
Genetic marker
Linkage study
Association study
70
Lifetime prevalence (%)
Term
The set of genes inherited by an individual; usually used in reference to the set of genes related to the phenotype of interest A known location in the DNA sequence at which there is variation between individuals; this can be used to track genes within the population or within families
Polymorphism
A position in the DNA sequence that varies commonly between individuals in the population – they are therefore useful as markers
Single Nucleotide Polymorphism (SNP; pronounced ‘snip’)
A polymorphism in which the variation is at one of the nucleotide bases
Linkage disequilibrium
When used in psychiatric genetics this usually refers to assocation between a variant of a genetic marker and disease – this implies close proximity of the marker to the disease gene
30 20 10 (Pop)
(Sib)
(MZ)
(Pop)
(Sib)
(MZ)
Unipolar disorder
Pop, population; Sib, sibling of a proband; MZ, monozygotic co-twin of a proband.
2
by estimates of heritability, typically in the region of 80–90% for bipolar disorder and 30–40% for major depression.
Mode of inheritance Having established that genes play a role in mood disorder, what sort of genetic model might we anticipate? In a small number of families it is possible that illness may be determined primarily by a single gene; however, for most mood disorder in the population it is likely that several, or many, genes are involved. The most plausible genetic models involve interaction and co-action between multiple genes together with environmental factors. It is probable that some genes confer risk to both bipolar and unipolar illness whilst others confer specific risk to one or other of the major forms of mood disorder.
Molecular genetic studies Linkage and association studies using DNA markers are at the cutting edge of modern psychiatric genetics. Linkage studies use families in which more than one member is affected by disease, whereas association studies use unrelated affected probands and appropriate comparison individuals. Conceptually, molecular genetic studies can be divided into positional and candidate gene approaches. In positional approaches, the chromosomal locations of susceptibility genes are determined, usually by linkage studies. This requires no knowledge of disease pathophysiology and can be considered a purely genetic approach. This has obvious attractions for the study of psychiatric illnesses where pathogenesis is poorly understood. In contrast, the candidate gene approach presupposes that the researcher has sufficient understanding of disease biology to be able to recognize genes that may be involved in bipolar disorder. These are then examined in linkage or association studies. In practice, both positional and candidate approaches are often combined in a positional candidate approach. To date, substantially more molecular genetic research has been
1
they show that factors other than straightforward genetics must also play a role, with the twin concordance data being the most important evidence for this. Figure 2 shows the approximate recurrence risk estimates for major affective disorder in various classes of relative of a proband with either bipolar disorder or unipolar depression. The estimates of lifetime risk are taken from studies conducted over the past 30 years that have used the modern concept of bipolar and unipolar disorders. (These figures are approximate and illustrative. There are wide variations between estimates in individual studies, particularly of unipolar depression, reflecting variations in clinical populations and methods. Note that individuals with a bipolar relative are also at a substantially increased risk of unipolar depression compared with a member of the general population.) The genetic contribution to bipolar disorder is greater than that for unipolar depression, as demonstrated
PSYCHIATRY 5:5
40
Bipolar disorder
A study in which genetic markers are used within samples of unrelated individuals and some form of controls to locate disease susceptibility genes An association study in which a large set of markers (of the order of 500,000) is studied, distributed systematically across all chromosomes
50
0
A study in which genetic markers are used within sets of families multiply affected by illness to locate disease susceptibility genes
Whole-genome association study
60
171
© 2006 Elsevier Ltd
PATHOPHYSIOLOGICAL BASIS OF MOOD DISORDERS
undertaken in bipolar disorder that in unipolar depression, reflecting the increased effort that has been focused on the phenotype under greater genetic influence.
systems that are influenced by medications used in clinical management of the disorders. Variants in several well-known genes have received substantial attention and, for some of these (the genes encoding the serotonin transporter and the enzymes monoamine oxidase A (MAOA) and catechol-o-methyl transferase (COMT)), at least one meta-analysis of studies has shown evidence for association. However, estimated effect sizes are all small and overall significances are modest. It should be noted that, in the face of the small expected genetic effect sizes (odd ratios (OR) in the expected range (OR < 2)), a sample size of 500–1000 is required to provide adequate power to replicate. Such sample sizes are only just becoming routinely used in genetic studies. Thus, it is likely to be some time before the issue is definitively settled as to whether and to what extent polymorphisms within these genes contribute to the risk of bipolar illness. The two best supported genes of interest to emerge from recent studies of bipolar disorder are DAOA and BDNF. D-amino acid oxidase activator DAOA(G72)/G30 locus – at least five independent datasets contribute evidence that variation at the DAOA/G30 locus on chromosome 13q influences susceptibility to bipolar disorder. This locus was implicated originally as being involved in susceptibility to schizophrenia. It was a novel locus, with a designation of G72, which was found by positional studies. The locus was renamed as D-amino acid oxidase activator, DAOA, because biological studies suggested that the gene product activated the enzyme D-amino acid oxidase (DAO). In addition to the positive bipolar findings, association has been replicated in additional schizophrenia samples. No pathologically relevant variant has yet been identified and the biological mechanism remains to be elucidated. Brain-Derived Neurotrophic factor (BDNF) – a functional candidate gene that has attracted a great deal of recent interest is BrainDerived Neurotrophic factor (BDNF), located on chromosome 11p13. BDNF plays an important role in promoting and modifying growth, development and survival of neuronal populations and, in the mature nervous system, is involved in activity-dependent neuronal plasticity. These processes are prominent in the synaptic plasticity hypothesis of mood disorder. There have been three positive reports using family-based association studies of Caucasian bipolar disorder samples of European-American origin and a common amino acid-altering single nucleotide polymorphism (SNP): two were based on adult bipolar samples and one was based on a small childhood onset sample. In our own Caucasian bipolar case-control sample (N=3062) we found no overall evidence of allele or genotype association. However, we found significant association with disease status in the subset of cases that had experienced rapid cycling (4 or more episodes per year) at some time, and a similar association on re-analysis of our previously reported family-based association sample. This suggests that variation at BDNF may not play a major role in influencing susceptibility to bipolar disorder as a whole but, rather, may be associated with susceptibility to a specific aspect of the clinical bipolar phenotype.
Bipolar disorder Linkage studies: after early difficulties in which apparently promising findings based on a search for major genes could not be replicated, the research field has moved forward using methodologies more appropriate for the study of complex genetic traits. At least 20 systematic genome screens have been conducted on a variety of sample sets, ranging from single large densely affected pedigrees in genetic isolates to samples comprising several hundred affected sib pairs. The pattern of findings is consistent with there being no single gene of major effect to explain the majority of cases of bipolar disorder and with that expected in the search for genes for a complex disorder: several broad chromosomal regions of interest have emerged; no finding replicates in all datasets; and for individual positive findings levels of statistical significance and estimated effect sizes are usually modest. The field has reached sufficient maturity that meta-analyses and combined analyses of genome scans have been undertaken. Figure 3 shows chromosomal regions that have been identified in at least one genome scan as showing evidence for linkage that is significant at the genome-wide level (a stringent level of statistical significance that takes account of testing markers across the whole genome). It should be noted that additional regions have been implicated by multiple studies showing evidence at a lower level of significance.5 Association studies: good candidate gene studies depend critically on the choice of good candidates – this inevitably depends on the current understanding of disease pathophysiology. Most of the earlier candidate gene studies focused on neuro-transmitter
Chromosome regions that have achieved genomewide significant linkage in linkage genome scans of mood disorders* Chromosomal region
Bipolar disorder
Unipolar depression
1q42
+
2p13
+
4p16
+
4q32
+
6q21-q25
+
8q24
+
12q22–q24
++
15q14
+
15q25–q26
Schizoaffective disorder, bipolar type
+ +
Unipolar disorder Linkage studies: family members of bipolar probands who themselves suffer with unipolar depression have been included in the broad phenotype in most studies of bipolar disorder. However, compared with bipolar disorder and schizophrenia, relatively few
+, one study; ++, two studies. *Several other chromosomal regions are implicated through multiple studies showing linkage signals at a lower level of signifiance.
3
PSYCHIATRY 5:5
172
© 2006 Elsevier Ltd
PATHOPHYSIOLOGICAL BASIS OF MOOD DISORDERS
genome scans of unipolar disorder as the main phenotype have been conducted to date and there have been no meta-analyses undertaken. However, linkage signals significant at a genome-wide level have been reported (see Figure 3).
Management implications of identifying susceptibility genes The schematic diagram below shows the probable development of changes affecting clinical management. It may be possible to start better tailoring of existing treatments to patients’ individual needs in the near future. The development of effective new treatments and prophylactic interventions is likely to take many years.
Association studies: as with linkage studies, to date, less attention has been given to genetic association studies of unipolar disorder than has been the case for bipolar disorder or schizophrenia. There are no unambiguous positive findings but the literature is developing rapidly. Given the expected smaller effect sizes and the possibility of greater clinical heterogeneity in unipolar disorder compared with bipolar disorder and schizophrenia, it can be expected that larger samples are likely to be required both for detection and replication of susceptibility loci. Perhaps the most interesting finding to emerge to date is the report of interaction between a functional variant at the serotonin transporter gene and the occurrence of life events in early adulthood.6 There have been both positive and negative attempts at replication. It is widely assumed that gene–environment interactions and co-action will occur in mood disorder and this finding may prove to be the first such example, although robust replication is required.
Treatment implications Now
Future 4
Molecular genetics and the Kraepelinian dichotomy Traditionally, psychiatric research in general, and the search for predisposing genes in particular, has proceeded under the assumption that schizophrenia and mood disorder are separate disease entities with separate underlying aetiologies (and treatments) – the so-called ‘Kraepelinian dichotomy’. However, molecular genetic studies are challenging this view. Several chromosomal regions have been implicated by linkage studies of both bipolar disorder and schizophrenia. Of particular interest is a genome scan of schizoaffective disorder, bipolar type, which showed genome-wide significant linkage (Figure 3) and supports the existence of one or more genes that influence susceptibility to a ‘third psychosis’. Most convincingly, several recent reports implicate variation at the same loci as influencing susceptibility to both schizophrenia and bipolar disorder. For example, the best supported locus for bipolar disorder is DAOA, which was originally identified in studies of schizophrenia. Other genes for which there is evidence of association for both disorders include Disrupted In Schizophrenia 1 (DISC1), COMT and Neuregulin 1 (NRG1). Such findings provide strong evidence (which is consistent with family and twin data) that there are genetic loci that contribute susceptibility across the Kraepelinian divide to schizophrenia, bipolar disorder and schizoaffective disorders. This has important implications for classification of the major psychiatric disorders because an overlap has been demonstrated in the biological basis of disorders that, over the last one hundred years, have been assumed to be distinct entities. Molecular genetic findings allow a re-appraisal of psychiatric nosology as well as providing a path to understanding the pathophysiology that will facilitate development of improved treatments. Rather than classifying psychosis as a dichotomy, a more useful formulation may be to conceptualize a spectrum of clinical phenotype with susceptibility conferred by overlapping sets of genes.
studies of mood disorders. Replications of current findings in large, well-characterized samples are required to determine their robustness and generalizability. It will be necessary to undertake detailed phenotype–genotype studies across the mood–psychosis spectrum, as well as functional biological studies to determine how biological variation influences clinical phenotype. It can be expected that some current findings will prove to be false positives and there will be many more susceptibility or disease-modifying genes to be identified in future studies. New methodologies, including whole-genome association studies, can be expected to complement existing approaches to facilitate progress.
Clinical, psychosocial and ethical issues Identification of susceptibility and modifying genes for mood and psychotic disorders has the potential to radically change the practice of psychiatry, alter the perception of mental illness and greatly enhance the understanding and treatability of some of the common major illnesses that afflict populations around the world. One of the earliest clinical benefits is likely to be better recognition of clinically and biologically homogeneous groups, with a consequent improved ability to tailor existing treatments to the individual patient. The likely time course for other developments is shown in Figure 4. Some of the advances will be accompanied by important ethical and psychosocial issues, including availability of new technology, access to genetic information and the subtle shift from a simple doctor–patient relationship to a doctor–patient–family relationship. It will be essential that an informed and balanced approach is taken to address these so that major advances in scientific understanding can be translated into major advances in clinical care.
Conclusions A robust body of classical genetic data indicates the existence of susceptibility genes in mood disorders. The current positional and candidate molecular genetic studies are producing replicable
The future Positive findings are beginning to emerge from molecular genetic
PSYCHIATRY 5:5
• More precise tailoring of existing treatments to individual patient profiles • Greater use of medication for clinical dimensions rather than diagnoses • New treatments based on deeper understanding of pathogenesis and better models • Prophylactic interventions
173
© 2006 Elsevier Ltd
PATHOPHYSIOLOGICAL BASIS OF MOOD DISORDERS
results. The best supported genes for bipolar disorder are DAOA and BDNF, and for unipolar depression the gene encoding the serotonin transporter. Evidence is accumulating that challenges the traditional Kraepelinian dichotomy. It is likely that many susceptibility genes will be discovered and characterized in the next few years and this will greatly enhance our understanding of disease pathogenesis and psychiatric nosology. Consequently, this has the potential to lead to a revolution in clinical psychiatry which will benefit psychiatrists, patients and their families. It is also extremely important to recognize that there are a number of ethical issues that will accompany these developments, and these will need to be considered very carefully.
REFERENCES 1 Tsuang M T, Faraone S V. The genetics of mood disorders. Baltimore: Johns Hopkins University Press, 1990. 2 McGuffin P, Katz R. The genetics of depression and manic-depressive disorder. Br J Psychiatry 1989; 155: 294. 3 Craddock N, Jones I. The genetics of bipolar disorder. J Med Genet 1999; 36: 585–94. 4 Sullivan P F, Neale M C, Kendler K S. Genetic epidemiology of major depression: review and meta-analysis. Am J Psychiatry. 2000; 157: 1552–62. 5 Craddock N, O’Donovan M C, Owen M J. The genetics of schizophrenia and bipolar disorder: dissecting psychosis. J Med Genet 2005; 42: 288–99. 6 Caspi A, Sugden K, Moffitt T E et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 2003; 301: 386–9. FURTHER READING Bishop T, Sham P. Analysis of multifactorial disease. Human molecular genetics. London: BIOS Scientific Publishers Ltd, 2000. Craddock N, Forty L. The genetics of affective (mood) disorders. Eur J Hum Genet, forthcoming. Craddock N, Owen M J. The beginning of the end for the Kraepelinian dichotomy. Br J Psychiatry 2005; 186: 364–6. Jones I, Kent L, Paul M, Craddock N. Clinical implications of psychiatric genetics in the new millennium – nightmare or nirvana? Psych Bull 2001; 25: 129–31. McGuffin P, Owen M, Gottesman I I. Psychiatric genetics and genomics. Oxford: Oxford University Press, 2002. Nuffield Council on Bioethics. Mental disorders and genetics: the ethical context. London: Nuffield Council on Bioethics, 1998. Plomin R, DeFries J C, McClearn G E, McGuffin P. Behavioral genetics: a primer. 4th edition. New York: W H Freeman and Company, 2001.
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