Clinical applications of schizophrenia genetics: genetic diagnosis, risk, and counseling in the molecular era

Figures & data

Table 1 Schizophrenia within the context of other common complex neuropsychiatric diseases (as of 2011)

	Schizophrenia	ASD	Epilepsy	Parkinson disease	Alzheimer disease
Clinical features
Approximate lifetime risk	~1%	~1%	~0.5%	~1.6%a	~10%a
Typical onset	Young adulthood	Early childhood	Childhood	Mid to late adulthood	Mid to late adulthood
Clinical heterogeneity	Yes	Yes	Yes	Yes	Yes
Clinical diagnostic imaging/biomarker(s)/test(s)	No	No	Yes	No	No
Definitive neuropathological diagnosis	No	No	No	Yes	Yes
Primary mode of neuropathogenesis	Developmental	Developmental	Developmental	Degenerative	Degenerative
Genetic features
Heritability	>80%	~90%	~45%b	~30%	~70%
Genetic heterogeneity	Yes	Yes	Yes	Yes	Yes
Major common variant(s)	No	No	No	No	Yes
Rare sequence mutation subtype(s)	No	Yes	Yes	Yes	Yes
Rare chromosomal anomaly/structural mutation subtype(s)	Yes	Yes	Yes	No	Yes
Genetic diagnosis changes medical managementc	Yes	No	Yes	No	No
Pharmacogenetics as standard of care	No	No	No	No	No
Routine use of genome-wide scansd	No	Yes	No	No	No
Family history as predominant recurrence risk factor	Yes	Yes	Yes	Yes	Yes
Sources (reference numbers)	See text^Citation9	^Citation61, ^Citation190, ^Citation233, ^Citation234	^Citation235^–^Citation239	^Citation240^–^Citation243	^Citation244^–^Citation247

Notes:

a Estimated based on risk after age 55–65 years, and therefore highly dependent on the mean life expectancy of the population;

b no consensus estimate, with a wide range of reports in the literature;^235,239

c management changed for the associated neuropsychiatric disease; this does not include more informed genetic counseling, the precipitation of other referrals or investigations,²⁴⁸ or the potential for earlier/more aggressive treatment as a result of early clinical diagnosis because of an increased index of suspicion;

d without accompanying developmental delay/mental retardation, ASD, or multiple congenital anomalies.

Abbreviation: ASD, autism spectrum disorder.

Table 2 Potential future roles for molecular genetics in the clinical management of schizophrenia

Area of benefit	Details and examples
Medical (of primary benefit to the clinician and patient)
Prediction and prevention	Personalized genetic (ie, inborn) lifetime risk for psychosis* Narrowing of window for age at onset in high risk cases Personalized neurocognitive and/or neuroimaging precursors of psychosis Opportunity to limit important deleterious gene by environment interactions Anticipation of potential extra-psychiatric features* Tailored early interventions to delay or prevent onset, or attenuate course
Diagnosis	At first onset of psychosis, higher index of suspicion for schizophrenia (as a result of improvements in prediction)*
Management	Coordinated multisystem management and anticipatory care for possible extra-psychiatric manifestations of causal genetic variant(s)*
Treatment	Earlier/more aggressive treatment (as a result of improvements in prediction and diagnosis)* Preference for or avoidance of particular antipsychotic medications Tailored dosing (eg, via knowledge of fast and slow metabolizers; pharmacogenomics) Less potential confusion of medication side effects with extra-psychiatric manifestations of causal genetic variant(s) (eg, metabolic syndrome, parkinsonism, seizures)* Novel personalized therapeutic targets
Prognosis	Improved course (as a result of improvements in prediction/prevention, diagnosis, treatment, and management)* Personalized data on natural history and longevity*
Psychosocial (of primary benefit to the patient and family)
Understanding	Partial answer to the question, “Why me?”* Explanation for potential premorbid developmental signs and symptoms (eg, learning difficulties)* Extra reassurance that parenting or personal life choices did not play a major role in causing the illness*
Counseling	Personalized recurrence risks for family members* Better informed reproductive decision making and possibility for prenatal detection*
Hope	Proof of progress in understanding the illness* Prospect of continued improvements in treatment and management, as above*

Note:

* Already possible for 22q11.2 deletion syndrome (22q11.2DS) subtype of schizophrenia (see text for details).

Table 3 The current established and emerging genetic subtypes of schizophrenia are characterized by large, rare, recurring copy number variation and variable expressivity

Genetic subtype of schizophrenia	Established	Emerging
Genotype
Locus	22q11.2	1q21.1	3q29	15q11-q13	15q13.3	16p11.2
Copy number change	Loss	Loss	Loss	Gaina	Loss	Gain
Typical size	3.0 Mb	1.4 Mb	1.6 Mb	6.0 Mb	1.5 Mb	0.6 Mb
Phenotypeb
MIM number	188400/192430	612474	609425	608636	612001	611913
Schizophrenia	Yes	Yes	Yes	Yes	Yes	Yes
Other psychiatric illnessesc	Yes	Yes	Yesd	Yesd	Yes	Yes
ASDs	Yes	Yesd	Yes	Yes	Yes	Yes
Developmental delay/mental retardation	Yes	Yes	Yes	Yes	Yes	Yes
Seizures/epilepsy	Yes	Yes	Noe	Yes	Yes	Yes
Congenital anomaliesf	Yes	Yes	Yes	Noe	Yes	Yes
References	See text^Citation46	^Citation64, ^Citation159, ^Citation163, ^Citation164, ^Citation166, ^Citation168, ^Citation170, ^Citation172, ^Citation173, ^Citation175, ^Citation249^–^Citation254	^Citation64, ^Citation161, ^Citation162, ^Citation166, ^Citation255^–^Citation261	^Citation64, ^Citation127, ^Citation157, ^Citation159, ^Citation160, ^Citation180, ^Citation262^–^Citation268	^Citation64, ^Citation159^–^Citation161, ^Citation164, ^Citation166, ^Citation173, ^Citation253, ^Citation254, ^Citation269^–^Citation278	^Citation64, ^Citation161, ^Citation164, ^Citation166, ^Citation173, ^Citation182, ^Citation253, ^Citation279^–^Citation288

Notes:

a Originating on maternally derived chromosome;

b there are no pathognomonic signs or symptoms, and the penetrance of each microdeletion or microduplication with respect to each component phenotype is incomplete;

c major depressive disorder, bipolar disorder, attention-deficit hyperactivity disorder/hyperactivity (unspecified), generalized anxiety disorder/anxiety (unspecified), aggression/temper outbursts, and/or major behavior problems (unspecified);

d rare reports only;

e no compelling data as yet, but there remain few detailed reports of the phenotype in individuals with this structural variant;

f cardiac anomalies, palatal anomalies (such as velopharyngeal insufficiency), skeletal abnormalities, and/or other major birth defects.

Abbreviations: ASDs, autism spectrum disorders; Mb, mega base pairs; MIM, Mendelian Inheritance in Man.

Table 4 Pathway to clinical utility for copy number variation and genomic disorders associated with schizophrenia (as of 2011)

Clinically relevant issues	Established genetic subtype	Emerging genetic subtypes	Potential susceptibility factorsa
	22q11.2 deletion	1q21.1 deletion 3q29 deletion 15q11-q13 duplication 15q13.3 deletion 16p11.2 duplication	Various, including: 1q21.1 duplication 15q11.2 deletion 16p13.11 duplication 17q12 deletion
Replication of association in unrelated cohorts	●	●	●
Estimation of population incidence and de novo vs inherited rates	○b	c	c
Estimation of prevalence within general schizophrenia population	●	○d	○d
Estimation of penetrance for schizophrenia (± for any feature)	●	○e	○e
Assessment of clinical expression of the schizophrenia illness	●
Elucidation of neuropsychiatric expression across the lifespan	●f	○g	○g
Elucidation of other expression across the lifespan	●f	○g	○g
Search for genetic modifiers of expression	○
Search for early clinical predictors of psychosis	○
Evaluation of transmission patterns and reproductive fitness	●
Development of clinical screening criteria	●
Evaluation of prognosis and long-term outcomes	○
Identification of opportunities for improved management	○
Creation of clinical practice guidelines	●
Description of treatment response (pharmacogenomics)	○h
Identification of specific treatment targets

Notes: See text and Table 3 for references.

a Seemingly less penetrant for schizophrenia, and/or with less evidence as yet for association, than the emerging genetic subtypes, see text for details;

b population incidence estimates based mainly on prevalence in infants with major congenital anomalies (eg, congenital heart disease²⁸⁹);⁵⁹

c one nonstandard attempt to estimate the de novo rate using available case-control data;²⁹⁰

d estimated from available case-control data;⁵ no studies of consecutive patients, nor any involving only a single centre or community catchment;

e attempts to estimate penetrance did not use standard genetic methods, but instead available case-control data;^64,291

f adults with 22q11.2DS may have a diminished lifespan;⁷⁵

g some data, primarily derived from association studies of other developmental diseases. Little to no data regarding lifelong expression (ie, in adulthood), or expression in carriers not ascertained through a major phenotype;

h clinical observation suggests that response to treatment is not substantially different in 22q11.2DS-schizophrenia,^9,43 but there remain limited published data.

● = Much evidence or progress; ○ = some evidence or progress.

Figure 1 Neurodevelopmental model of schizophrenia, informed by new molecular genetic discoveries. One or more transmitted or de novo sequence or structural mutations, involving one or more genes, and acting individually or interactively, is proposed as the initial causal event. The pathway from genotype to phenotype is formulated as a dynamic process beginning at or before conception, and involving gene expression (including, but not limited to, protein activity) and interaction with normal brain development and neuronal plasticity mechanisms, and likely multiple other genetic and non-genetic factors. Different phenotypic endpoints are possible, and specific factors that dictate variable expression of ostensibly the same genetic loading are largely unknown and may be variant-specific. These resulting phenotypes could include clinically diagnosable schizophrenia, other psychiatric illnesses, other conditions including disorders of development, or no detectable expression. For example, a 22q11.2 deletion (yellow structural variant) may be expressed as schizophrenia and/or a related psychiatric disorder and/or another developmental disorder (yellow stars).

Note: Adapted from AS Bassett, EW Chow, S O’Neill, LM Brzustowicz, Genetic insights into the neurodevelopmental hypothesis of schizophrenia, Schizophrenia Bulletin, 2001, 27, 3, pp. 417–430, by permission of Oxford University Press.³⁵
Abbreviation: CNV, copy number variation.

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