Patients With Genetic Syndromes

Epidemiology of Psychiatric Disorders

Twin, family, and adoption studies can assess the magnitude of genetic versus environmental factors that lead to a phenotype. Family studies usually measure the life-time prevalence of a disorder among first-degree relatives of the affected individual, known as the index case. Adoption studies can help further disentangle genetic and environmental influences by comparing rates of a disorder in biological family members with those in adoptive family members. In addition, comparing rates of a disorder in twins that were raised in the same household with twins reared in separate households can provide further evidence about the genetic and environmental influences that lead to expression of the disorder. For example, comparing concordance rates in monozygotic twins raised apart (in different environments) can provide an estimation of the heritability of a disorder, as these individuals have near identical DNA and differ primarily in their environment.

Heritability estimates the extent to which differences in the appearance of a trait across a population can be accounted for by genetic factors. Heritability is measured on an index from 0 to 1; a heritability index of 1 means that 100% of the variability between individuals in a population is due to genetic factors (i.e., there is no environmental contribution). It is an estimate of the additive sum of all the genetic influences on a trait in the population. A helpful conceptualization of the heritability index is that all traits exist on a continuum from “genetic” to “environmental,” with most traits receiving influence from both factors.

Heritability says nothing about the likelihood of a particular individual to inherit a gene, nor about the number of genes that are involved in a trait or the effect size of a given gene. Thus, if the heritability of bipolar disorder is 0.75, this indicates that 75% of the variability observed in those with bipolar disorder is due to genetic causes but does not suggest that a particular individual has a 75% chance of developing bipolar disorder.

As Table 35-1 demonstrates, both genes and environment contribute substantially to the expression of psychiatric disorders, more so for major depressive disorder (MDD) than for schizophrenia or autism, and the relationship between genetic and environmental influences is far more complicated than a simple linear relationship. Environmental factors that contribute to the expression of these disorders include early life events, stressful life events, difficult family environments, exposure to toxins and infectious agents, and a dysregulated immune system.

Gene-by-Environment Interactions

Gene-by-environment interaction is the tendency of two different genotypes to respond to environmental influences in different ways. In some cases, sensitivity to a particular risk factor for a disease may be inherited rather than the disease itself being inherited.

This gene-by-environment interaction was demonstrated in an often-quoted 2003 study of the interaction of the serotonin transporter gene and stressful life events in the onset of episodes of MDD. The serotonin transporter is the target of selective serotonin re-uptake inhibitor (SSRI) antidepressants. There is a common polymorphism in the promoter of the serotonin transporter gene that leads to a “long” allele or a “short” allele lacking a 44 base-pair sequence. The short allele is associated with a reduced expression of the serotonin transporter. The 2003 study by Caspi and colleagues examined a birth cohort of 1037 children followed to age 26 years for evidence of a linkage between the short or long allele of the serotonin transporter gene, stressful life events, and MDD. Stressful life events included problems in employment, financial, housing, health, and relationships. In the absence of stressful life events, the presence of either the short or long allele of the serotonin transporter gene was not associated with depressive symptoms in these individuals. However, with an increasing number of stressful life events, individuals with the short allele of the serotonin transporter gene, compared with those with the long allele, have an increasingly greater number of major depressive episodes, depression symptoms, suicidal thoughts, and suicide attempts. In addition, individuals with the short allele had an increased probability of adult major depressive episodes with increasing childhood maltreatment, whereas individuals with the long allele did not have more adult depression with childhood maltreatment. In both of these examples, individuals heterozygous for the short and long alleles had an intermediate phenotype compared with individuals homozygous for the short or long allele. These experiments show how an environmental factor, such as stressful life events, interacts with the genetic background of an individual, in this case a functional polymorphism in the serotonin transporter gene, to lead to psychiatric disorders such as MDD.

A second study, also conducted by Caspi and colleagues, highlights the effects of childhood trauma in the context of a functional polymorphism in the monoamine oxidase A (MAO _A ) gene promoter. The MAO _A promoter has been shown to moderate the association between exposure to early childhood trauma and the development of antisocial or aggressive personality traits. Among children with low MAO _A levels, childhood abuse is associated with higher levels of aggression and antisocial traits, whereas high levels of MAO _A appear to be partially protective against development of these traits even among childhood abuse victims.

Advances in Identification of Genetic Mutations that Underlie Psychiatric Disorders

A major current undertaking in psychiatric neurosciences is to identify genomic regions that influence psychiatric disorders and will provide opportunities for diagnostic accuracy, mechanistic clarification, and treatment precision. While some disorders are due to single dominant genes, such as the role of the methyl-CpG-binding protein 2 (MeCP2) , which is implicated in 95% of Rett syndrome cases, a leading hypothesis for many psychiatric disorders is that multiple risk genes of small effect size interact with one another, and at times with environmental factors, to lead to the disease phenotype. Several approaches commonly used by scientists to identify genes linked to psychiatric disorders are elaborated here.

The candidate gene approach focuses on selecting one or a small group of genes believed to be implicated in a disease. This approach relies on a strong hypothesis that a gene's function is likely to be involved in a disease mechanism. For example, studies of the serotonin transporter gene and its role in MDD were derived from pre-existing knowledge that serotonergic function was implicated in depression. Targeted studies of this gene revealed that mutations in the serotonin transporter gene lead to higher rates of depression within the population. These studies focus on a small number of specific genes and as such, they are often faster and less expensive than whole genome studies (discussed below). However, this approach is often not effective for diseases without background knowledge, or for those caused by the combined effect of multiple genes. Candidate gene approaches may utilize techniques such as fluorescence in situ hybridization (FISH) , a cytogenetic technique that uses fluorescent probes designed to bind complementarily to any gene of interest. These probes can localize anywhere on the chromosome a gene is located and detect deletions and/or duplications within that gene. Similarly, sequencing or SNP analysis is used for identification of gene mutations other than deletions or duplications.

In contrast, in a whole genome approach scientists sequence a near complete copy of an individual's genome to elucidate all mutations present in affected individuals as compared to healthy controls. This approach may identify unexpected genetic mutations anywhere in the genome that are implicated in disease pathology without requiring a priori knowledge of a particular gene's function. This higher identification rate is a mixed blessing; while it is more likely to identify the full spectrum of mutations involved in an illness it also yields more false-positives or mutations of unclear clinical significance that may cloud treatment decisions.

Another approach that has become increasingly utilized is genome-wide association studies (GWAS), in which hundreds or thousands of genomes are sequenced from individuals with and without a disease and compared with one another to identify genomic variations between these populations. Genomes may be compared between unrelated individuals, biological or adopted relatives, individuals of similar or different ethnicity, environment, or any number of parameters.

GWAS take advantage of the fact that, while most genes are fixed within a population, some genes, known as polymorphisms , contain variants within a population. Most polymorphisms exist as single base-pair changes within the gene in which one of the four nucleotide bases is substituted for another. These variations, known as single nucleotide polymorphisms (SNPs) , occur approximately once every 300 base-pairs, accounting for healthy genetic diversity within a population. However, GWAS studies reveal that particular SNPs may be more prevalent in certain disease phenotypes, suggesting that a certain SNP may be “associated” with the disease phenotype. Because SNPs occur normally within the population, GWAS require thousands of patients to achieve statistical power to see an association, and must consider factors such as race, gender, and geography to reduce false-positives. GWAS have been instrumental in elucidating genes that are likely implicated in mental illness. For example, GWAS identified over 108 loci that meet genome-wide significance for schizophrenia with sample sizes in some studies exceeding 36,900 subjects. Many of the identified genes are involved in regulatory functions that are impaired in schizophrenic patients including DRD2 (D ₂ dopamine receptor gene), TCF4 (a transcription factor involved in neurogenesis), NRGN (a post-synaptic protein kinase substrate involved in learning and memory), and ZNF804A (a transcription factor involved in regulating neuronal connectivity). Multiple genes involved in glutamatergic neurotransmission and synaptic plasticity were also implicated.

In addition to studying SNPs, GWAS have identified over 1000 copy number variants (CNVs) , which are duplications or deletions of genomic segments ranging from 1 kilobase to several million bases that in some cases are enriched in patients with schizophrenia, autism, and bipolar disorders. CNVs may be inherited from one or both parents, or may arise as new, or de novo , mutations in individuals. These CNVs may interrupt an implicated gene and may cause downshift mutations in later genes. A 2008 study showed that novel CNVs were present in 15% of 150 individuals with schizophrenia and only 5% of controls. Most of the structural variants identified were different and rare, and these variants disrupted genes important for brain development. A larger study of 3391 patients with schizophrenia found a 1.15-fold increased burden of CNVs in patients with schizophrenia than in controls, particularly rarer, single-occurrence CNVs. In addition, children with autism spectrum disorders have a significantly increased burden of de novo deletions and duplications.

Another important finding of GWAS has been the identification of genes that are shared between psychiatric disorders. For example, microduplications of 1q21.1 are associated with both autism spectrum disorder and schizophrenia, and microduplications of 16q11.2 are associated with autism spectrum disorder, schizophrenia, and bipolar disorder, yet individuals who have any one of these disorders are unlikely to have all three. These findings underscore the complex and polygenic etiology of many psychiatric disorders, and the current limitation of understanding how genetic susceptibility translates to phenotypic expression. Another compelling example of the overlapping genetic etiology of varying psychiatric disorders is the discovery of the gene called Disrupted-in-Schizophrenia-1 (DISC-1) in a large Scottish family with a high incidence of schizophrenia. This family had a balanced translocation between chromosomes 1 and 11, and DISC-1 was discovered at the breakpoint of this translocation. DISC-1 is involved in regulating brain development, neuronal migration, and a signaling pathway important for learning, memory, and mood. The translocation in this large extended Scottish family is associated with not only schizophrenia but with bipolar disorder and MDD. Genes, such as DISC-1 , that influence how the brain develops may impart a risk for multiple disorders. In the future, DSM diagnostic categories may be refined on the basis of findings about the genes involved in psychiatric disease.

Once genetic loci of interest have been identified, linkage studies are used to generate a logarithm of the odds score (LOD score), which estimates whether two or more genetic loci are perturbed or inherited with higher frequency in affected individuals than would be expected by random chance. An odds ratio of 1000 : 1 (corresponding to an LOD score of 3) is the typical threshold of linkage determination.

These findings may be verified or determined by a recently developed technique, multiple ligation dependent probe amplification (MLPA), which allows for detection of differences in genetic copy numbers, and can detect up to 50 different genes that differ by as little as one nucleotide.

An alternative approach is to determine the genetics of intermediate phenotypes or “endophenotypes,” in which symptoms manifest at a low level that does not meet criteria for acute mental illness. For instance, the polymorphism in the serotonin transporter gene discussed previously has been associated with increased amygdala reactivity and reduced coupling of corticolimbic circuits seen by neuroimaging. Another intermediate phenotype that is studied is the inhibition of P50-evoked responses to repeated auditory stimuli in schizophrenia.

Assessment of the Patient for Genetic Syndromes

Certain features of the medical history, family history, and physical examination may indicate the possibility of a genetic syndrome that underlies observed psychiatric symptoms. In addition to the comprehensive review of systems and medical history during the initial assessment of patients, inclusion of questions about pregnancy and the perinatal period, birth defects, and surgeries in infancy or early childhood that may have been performed to correct congenital anomalies may provide valuable clues to an underlying genetic syndrome. In addition, careful review of the developmental history (with special attention paid to early developmental milestones) may reveal the presence of specific developmental delays, intellectual disability, or learning disabilities. When inquiring about family history, the clinician should ask specific questions about recurrent miscarriages; stillborn children; early infant deaths; and a family history of intellectual disability, seizures, or congenital illness, which may help in uncovering an underlying genetic disease, especially when the pattern of illness appears to be Mendelian (e.g., dominant, recessive, or X-linked inheritance). Some standard assessment questions are summarized in Table 35-2 . In addition, careful physical examination may reveal abnormalities of growth, dysmorphic features, or involvement of various organ systems. Results of imaging studies may aid in the assessment of underlying malformations suggested by physical examination (e.g., echocardiogram to rule out structural heart defects when a murmur is appreciated, neuroimaging when neurological defects are detected).

Selected Genetic Disorders