Basic Neurosciences · Paper A
Classic candidate genes: SHANK3 (autism) and DRD4 (ADHD)
SHANK3 pairs with autism spectrum disorder and DRD4 with attention deficit hyperactivity disorder — and the moment you can say that, the more valuable half of this topic is knowing how little either pairing actually explains. SHANK3, on chromosome 22, makes a scaffolding protein that holds the machinery of an excitatory synapseThe tiny gap between two nerve cells where a chemical signal passes from one to the other.Read more → in place; losing it causes Phelan-McDermid syndrome, in which autism is common. DRD4 makes the dopamine D4 receptor, and its 7-repeat variant has a small, repeatedly reported association with attention deficit hyperactivity disorder. Both conditions are strongly heritable, but that heritability is spread thinly across very many variants rather than concentrated in one famous gene, which is why the field stopped picking candidates by hand and went genome-wide. Expect to be asked to match the pairs, and expect at least one option that quietly promotes a candidate gene into a cause or a test.
The two genes sit at opposite ends of the same spectrum of genetic effect, and understanding why explains everything else about them. SHANK3 encodes a scaffolding protein in the postsynaptic density — the dense cluster of proteins on the receiving side of an excitatory synapseThe tiny gap between two nerve cells where a chemical signal passes from one to the other.Read more →, where receptors have to be held in the right place for signalling to work at all. Lose one working copy of that gene, whether through a deletion at the tip of chromosome 22 or a mutation that breaks the protein, and synaptic architecture is disrupted from the start of development, which is why the resulting condition, Phelan-McDermid syndrome, is not a subtle risk shift but a recognisable clinical picture of developmental delay, intellectual disability, severely limited speech, low muscle tone and, in a large proportion, autism spectrum disorder. DRD4 works in an entirely different register. It encodes the dopamine D4 receptor, and the variant of interest is a 7-repeat form of a 48-base-pair sequence repeated a variable number of times inside the gene, which alters how the receptor responds to dopamine rather than removing anything. That kind of change nudges risk instead of determining it, and meta-analyses have put its odds ratioA measure comparing the odds of an outcome between two groups; 1 means no difference.Read more → near 1.4. Because a nudge that small can only be detected in very large samples, the early candidate-gene literature — small studies of one hand-picked gene at a time — was underpowered by design, and most of its findings failed to replicate. Genome-wide association studies, which test the whole genome in tens of thousands of people rather than one gene in a few hundred, replaced that approach and showed what had been missed: risk carried by very many common variants of individually tiny effect, with rare high-impact changes such as SHANK3 disruption accounting for a small minority of cases. DRD4 is one of the few candidates whose association survived that transition, which is exactly why it is still taught.
Two pairings turn up again and again in psychiatry teaching: SHANK3 with autism spectrum disorder, and DRD4 with attention deficit hyperactivity disorder. They are worth knowing, and an examiner may well ask you to match them correctly. They are also, on their own, a poor description of how either condition is inherited, and the gap between those two statements is what this page is really about. Learn the pairings, then learn precisely how little each one carries — because the second half is what turns a memorised pair into understanding.
A candidate gene is a gene somebody picked out in advance, on the strength of what the protein it makes does, and then tested for association with a condition. Nobody searched the whole genome; a researcher reasoned that a dopamine receptor ought to matter in a disorder treated with stimulants, and went looking there. SHANK3 makes a scaffolding protein (a structural protein whose job is to hold other proteins in position) in the postsynaptic density (the crowded patch of signalling machinery on the receiving side of an excitatory ). DRD4 makes the dopamine D4 receptor, and the variant of interest is a 7-repeat form of a short stretch of DNA repeated a variable number of times within the gene.
The commonest error here is treating a candidate gene as though it were the cause of the condition it is paired with. Neither SHANK3 nor DRD4 comes close.
Both conditions are strongly heritable: twin studies put the heritability (the share of the differences between people in a population that tracks their genetic differences) of attention deficit hyperactivity disorder at roughly 70 to 80%, and autism spectrum disorder in a similar range. That inherited liability is spread across a very large number of genetic variants, most of them common in the population and each shifting risk by a tiny amount, with a small number of rare, powerful changes on top. A single candidate gene is one item in that crowd, and knowing its name tells you almost nothing about any individual child.
Picture a crowdfunding campaign that has raised a hundred thousand pounds. Most campaigns get there through thousands of five-pound donations, no one of which you would bother to look up. A rare campaign gets there mainly because one person gave fifty thousand pounds in a single transfer.
Genetic liability to autism and to attention deficit hyperactivity disorder works the same way. For nearly everyone, the total is a sum of very many tiny contributions from common variants — which is what polygenic (risk built from very many genes at once, each adding a little) means. In a small minority, a single rare and powerful change carries much of the total on its own. DRD4 is a five-pound donation; SHANK3, when it is disrupted, is the fifty-thousand-pound transfer. Both are real donations to the same total, and confusing one kind for the other is the mistake this topic exists to catch.
Start with DRD4 and work the arithmetic through. Meta-analyses of the 7-repeat allele in attention deficit hyperactivity disorder have put the (a number saying how much the odds of an outcome shift between two groups) at around 1.4 — a genuine association, replicated more often than most candidate-gene findings, and still small.
For example, suppose the baseline risk in children is about 5%. Odds of 5 to 95 multiplied by 1.4 give odds of about 7.4 to 100, which converts back to a risk of roughly 7%. So a child carrying the allele goes from about a 5-in-100 chance to about a 7-in-100 chance. Nothing about that supports testing anyone, and it is why no clinic anywhere orders a DRD4 genotype.
SHANK3 is the other kind of donation. Deletions and disruptive mutations of SHANK3 at the end of chromosome 22 cause Phelan-McDermid syndrome, whose picture is global developmental delay, intellectual disability, absent or severely delayed speech, low muscle tone, and autism spectrum disorder in a large proportion of those affected. Here one change really does carry much of the liability. It is also rare: SHANK3 disruption accounts for well under 1% of autism overall.
Question writers build wrong answers here by shuffling gene names between disorders, so rehearse the correct owner of each before you meet them shuffled.
| Gene | What it is actually paired with |
|---|---|
| SHANK3 | Autism spectrum disorder, via Phelan-McDermid syndrome from 22q13 deletion or mutation |
| DRD4 | Attention deficit hyperactivity disorder, the 7-repeat allele, small effect |
| FMR1 | Fragile X syndrome — a repeat expansion causing intellectual disability, with autistic features common |
| MECP2 | Rett syndrome — a distinct condition with regression and hand-wringing stereotypies, mostly in girls |
| DISC1 | A pedigree-derived candidate for psychosis and mood disorder, not for either condition on this page |
Neither autism spectrum disorder nor attention deficit hyperactivity disorder has a genetic test, an imaging test or any biomarker; both diagnoses rest on a developmental history, direct observation and information from more than one setting. Genetic investigation has a narrower and real role: where a child with autism also has intellectual disability, dysmorphic features or congenital anomalies, chromosomal microarray (a test that scans the whole genome for missing or duplicated stretches of DNA) and fragile X testing are the standard first-line investigations, because they can identify a specific syndrome such as Phelan-McDermid or fragile X and change genetic counselling for the family. Testing DRD4, or any other small-effect candidate variant, has no clinical role at all.
There is no treatment aimed at SHANK3, at DRD4 or at any polygenic score, so management follows the condition rather than the genotype. In the UK that means NICE CG170 for autism in under-19s, which puts psychosocial interventions and support for the family first and reserves medication for specific coexisting problems rather than for core autistic features, and NICE NG87 for attention deficit hyperactivity disorder, which sets out environmental modification, parent training and, where indicated, stimulant medication as first-line drug treatment. Where a specific genetic syndrome is identified, the change in management is genetic counselling and syndrome-specific surveillance, not a different psychiatric treatment.
Two moves win this topic. First, get the pairing right without hesitating: SHANK3 to autism, DRD4 to attention deficit hyperactivity disorder, and be ready for FMR1, MECP2 and DISC1 offered as decoys. Second, refuse any option that promotes a candidate gene into a cause, a test or a treatment target. Can you explain, in one sentence each, why SHANK3 matters clinically in a way DRD4 does not, and why neither is worth genotyping in a routine clinic?
Carry this away: SHANK3 goes with autism and DRD4 with attention deficit hyperactivity disorder, but one is a rare large-effect change that causes a recognisable syndrome and the other is a small-effect common variant among thousands, so the pairing is worth memorising and the causal story behind it is not.