Why is schizophrenia so common?
It afflicts more than 1 in 200 people.
It is highly heritable.
And it dramatically lowers fitness.
“There is little doubt about the existence of a
fecundity deficit in schizophrenia. Affected
individuals have fewer children than the
population as a whole. This reduction is of the
order of 70% in males and 30% in females. The
central genetic paradox of schizophrenia is why,
if the disease is associated with a biological
disadvantage, is this variation not selected out?
To balance such a significant disadvantage, a
substantial and universal advantage must exist.
Thus far, all theories of a putative advantage
have been disproved or remain unsubstantiated.”
– From the Wikipedia article “Schizophrenia”
“Data from a PET [positron
emission tomography] study
suggest that the less the
frontal lobes are activated
(red) during a working memory
task, the greater the increase
in abnormal dopamine activity
in the striatum (green),
thought to be related to the
neurocognitive deficits in
schizophrenia.”
Anth/Biol 5221, 7 December 2009
And the heritabilities are amazing! (Thank you, twins!)
Note that several conditions
considered distinct “diseases” by
mental-health professionals are
strongly correlated genetically
(MZ twins are diagnosed with
different ones of them much
more often than are DZ twins).
This has fueled debate about the
reality of the distinctions.
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What is the genetic basis of these susceptibilities?
Mutations in a few genes with large effects?
If so, which genes are they?
Or is it polymorphisms at many loci, each making a small contribution?
And in either case, what kinds of mutations are involved?
Unconditionally deleterious?
Or good-news/bad-news tradeoffs?
Amino-acid and nucleotide substitutions?
Or duplications and deletions (copy-number variation)?
QTL mapping studies
suggest that there
are genes with major
effects on many
chromosomes
2
There are a number of plausible “candidate” genes
Many of these play well
established roles in
neurotransmission, in or
near synapses.
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But there’s a big problem:
The major-effect genes explain just a fraction of the heritability!
Where’s the rest of it?
Could susceptibility be a highly polygenic quantitative trait?
This was proposed
more than 25
years ago by
Irving Gottesman.
But if that’s the case,
where is all this heritable
variation hiding?
And why is there so much
of it, given that selection
against schizophrenia is
very strong?
American Journal of
Human Genetics 35,
1161-1178 (1983)
One possibility:
frequent copynumber mutations
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But there are other possibilities, for example:
(1) very many genes with alleles of very small effect
(2) very many genes with alleles of infrequent effect (low penetrance)
(3) complex genetic interactions (epistasis, dominance, etc.)
(4) epigenetics (imprinting or other environmental “pseudo-heritability”)
However, not all of these are good at explaining the very high levels of
heritability seen in the twin studies and other direct pedigree analyses.
Could our great susceptibility to schizophrenia and related disorders be,
in part, a transitory side effect of recent rapid mental evolution?
If so, is Wikipedia’s assertion necessarily correct?
“The central genetic paradox of schizophrenia is why, if the disease
is associated with a biological disadvantage, is this variation not
selected out? To balance such a significant disadvantage, a
substantial and universal advantage must exist.”
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