2 Neuroscience2.9 Genetics

2.9.2 Links between neurotransmitter systems and findings from genetic association studies in psychiatry

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Written by Resident Doctor Committee · Published

What association studies show

  • Association studies compare genetic variation across phenotypes; they find risk signals, not transmitter levels or the cause of one person's illness.

  • Psychiatric liability is polygenic and shaped by environment.

  • Candidate gene studies chose genes from existing theories, often in samples too small for realistic effects, so many findings failed replication.

  • Genome-wide association studies test variation across the whole genome, usually with a significance threshold of p < 5 × 10^-8.

  • The 2022 Psychiatric Genomics Consortium schizophrenia study reported 287 loci from about 77,000 cases.

  • A locus does not name the causal gene, because linkage disequilibrium ties neighbouring variants together.

A Manhattan plot charts each variant's log10(p) value against its chromosomal position, with peaks rising above the dashed significance threshold marking associated loci. Genome wide association studies of schizophrenia report hundreds of such loci. M. Kamran Ikram et al, CC BY 2.5, via Wikimedia Commons

Schizophrenia candidate genes

Neuregulin and dysbindin are the classic schizophrenia susceptibility genes. Neuregulin is not neuroligin, a similar-sounding gene that belongs to another disorder.

Gene

Locus

What it does

NRG1 (neuregulin 1)

8p12

Growth factor signalling through ErbB4; shapes neurodevelopment; in excess suppresses NMDA receptor function

DTNBP1 (dysbindin)

6p22

Acts presynaptically; reduced expression lowers glutamate release; protein works in lysosome-related organelles

DISC1

1q42

Protein binds NDEL1 and PDE4B to steer cortical development

DAOA (G72)

13q

Activates D-amino acid oxidase, which breaks down D-serine and leaves NMDA receptors underactive

RGS4 (regulator of G-protein signalling 4)

1q23

Speeds GTP hydrolysis, ending dopamine and metabotropic glutamate receptor signals; prefrontal expression is reduced post-mortem

CHRNA7 (alpha-7 nicotinic receptor subunit)

15q13 to 15q14

Linked to the P50 sensory gating deficit

  • Dysbindin was first reported in Irish families.

  • DISC1 was found through a balanced t(1;11) translocation that tracked with psychosis and mood disorder in one Scottish pedigree, with the breakpoint cutting through the gene.

  • Nicotine briefly normalises the P50 deficit, one reason heavy smoking in schizophrenia is read as self-medication.

The 22q11.2 deletion and COMT

  • COMT lies within the 22q11.2 segment deleted in velocardiofacial (DiGeorge) syndrome, and is itself a schizophrenia candidate gene.

  • The deletion removes one copy of COMT, lowering catechol-O-methyltransferase, which methylates and inactivates dopamine.

  • The loss matters most in prefrontal cortex, where dopamine reuptake is sparse; this is the proposed route to psychosis.

  • The deletion involves many genes, so COMT alone does not explain the raised psychosis risk.

Compare the single transporter (DAT) in prefrontal cortex with the dense transporters in striatum: where reuptake is sparse, COMT does much of the clearing, so losing one copy of COMT matters most in prefrontal cortex. Drawn for MRCPsychiatrist

The serotonin transporter

  • SLC6A4 encodes the sodium-dependent serotonin transporter.

  • Its 5-HTTLPR promoter polymorphism has short and long alleles; the short allele reduces transporter expression.

  • The short allele is linked to neuroticism, anxiety and depression after stressful life events, though strong early claims failed replication.

  • SLC6A4 has never been a leading schizophrenia susceptibility gene.

Calcium channels and wider findings

  • Among voltage-gated cation channel genes, the calcium channel subset carries the strongest common-variant association with schizophrenia.

  • CACNA1C encodes the pore-forming alpha-1C subunit of Cav1.2, the main neuronal L-type voltage-gated calcium channel.

  • CACNA1C and CACNB2 findings cross diagnostic boundaries.

  • Genome-wide loci include transmitter genes such as DRD2 and GRIN2A, while pathway enrichment points to synaptic, channel and developmental genes.

  • C4 variation links schizophrenia risk to complement biology and a synaptic pruning hypothesis.

  • Polygenic scores summarise measured risk but are neither diagnostic nor assays of neurotransmission.

Revision material for the MRCPsych examinations. Not clinical guidance, and not for use in patient care.