Slides to accompany RALLIcampaign YouTube presentation by Professor Dorothy Bishop on Genetics and SLI A full-length videoed lecture on this topic can be found here: http://podcasts.ox.ac.uk/languages-disorders-children-what-can-they-tell-us-about-genes-and-brains-video OR audio version here: http://podcasts.ox.ac.uk/languages-disorders-children-what-can-they-tell-us-about-genes-and-brains-audio

1. Genetic influences on specific
language impairment
Dorothy Bishop
University of Oxford

2. SLI runs in families
Rates of language/learning difficulties higher
in relatives of those with SLI, compared with
controls of similar background
SLI control
50
40
% affected 30
relatives 20
10
0
Neils, Bishop, Tallal, Tomblin,
1986 1986 1989 1989

3. Twin Study Method
Monozygotic (MZ) twins:
genetically identical
Dizygotic or non-identical(DZ) twins:
For genes that vary between people,
have identical version for 50%

4. Twins growing up together
• Twins usually share lots of influences: e.g. how much TV they
watch, how much parents talk to them, who is caregiver in early
years, diet, family income, etc.
• These environmental influences will make twins similar to one
another. If they are important, twins should resemble one another,
regardless of whether MZ or DZ.
• If genetic influences are important, MZ twins should be similar to
one another, because they are genetically the same. DZ twins
have 50% genes in common, so will resemble each other, but less
so than MZ.

5. Study of twins growing up together
Diagnosis in co-twins of probands
with specific speech/language impairment (SSLI) Yellow area shows
SSLI low language speech therapy mental the proportion of twin
handicap pairs where both
twins had SLI. This is
greater for MZ than
DZ.
White area shows
proportion where one
twin had SLI and the
other had no
difficulties: much
greater for DZ than
MZ: n = 63 DZ: n = 27 MZ.
Bishop, D. V. M., North, T., & Donlan, C. (1995). Genetic basis of specific language
impairment: evidence from a twin study. Developmental Medicine and Child
Neurology, 37, 56-71.

6. A family tree that suggested there was a ‘gene for SLI’
Grandparents
Parents
Children
Black = Speech/language impairment
If you have an affected parent,
you have 50% chance of
having SLI
KE family
Hurst, J. A., Baraitser, M., Auger, E., Graham, F., & Norell, S. (1990). An extended
family with a dominantly inherited speech disorder. Developmental Medicine and Child
Neurology, 32, 352-355.

7. Finding the gene
• FOXP2: gene on chromosome 7q31: Found a change in a
single DNA base in affected individuals
• The DNA change in the KE family is very unusual.
Studies of the general population show that most people
have the same DNA sequence.
• The change in the KE family is a “missense mutation” –
the DNA sequence change alters how the gene operates,
so that it won’t be able to produce as much protein as it
normally does
Fisher, S. E. (2005). Dissection of molecular mechanisms underlying speech and
language disorders. Applied Psycholinguistics, 26, 111-128.

8. But KE family - not typical SLI
• Case of FOXP2 led to expectation that we might find
clearcut genetic mutations to explain all severe
language impairments
• Many other cases of SLI tested: very rare to find any
mutation of FOXP2
• Most language impairments behave like “complex
multifactorial disorders”

9. Complex multifactorial
disorders
Aggregate but do not segregate in families
– i.e. run in families but you can’t trace effect of gene
through the generations according to classic
Mendelian genetics
Many common medical conditions
behave this way, e.g. allergies, asthma,
high blood pressure, diabetes
9

10. Idea of underlying continuum
Low
Several genes, each
with a small effect,
combine with
environmental risks
to influence
observed behaviour
across
the whole range
High 10

11. Tracking down genes associated with SLI
• Compare language scores of people with different genotypes
• E.g. study by Newbury et al (2009) found two genes on chromosome 16
associated with poor phonological short-term memory (NWR score) in a
language-impaired sample
Very different
from FOXP2.
‘Risk’ alleles
common in
general population
and have small
effect size
Gene 1: CMIP Gene 2: ATPTC2
Newbury, D., et al. (2009). CMIP and ATP2C2 modulate phonological short-term
11
memory in language impairment. American Journal of Human Genetics, 85, 264-272

12. Same gene often associated with
many different disorders
CNTNAP2 gene – downstream target of FOXP2
Common variants of the gene associated with:
• Autism
• Specific Language Impairment
• Dyslexia
• ADHD
• Schizophrenia
• Age at language acquisition in general population
N.B. Effect sizes are SMALL. Not useful for genetic screening
Kang, C., & Drayna, D. (2011). Genetics of speech and language disorders.
Annual Review of Genomics and Human Genetics, 12, 145-164.

13. Why so much variation?
• An analogy: tuberous sclerosis – the same mutation
can lead to major brain malformation or minor
problems with skin
• Genes associated with language impairment likely
to affect very early neural development
• Precise impact may depend on which neuronal
areas affected, which may depend on:
1. Other genes (effects may be interactive)
2. Environmental factors
3. Random effects
See:
http://wiringthebrain.blogspot.co.uk/2012/06/probabilistic-inheritance-and.html13

14. Genetics: common
misconceptions
• Genes are the NO! even in MZ twins,
only thing that find different severity
matter
NO! genetic analysis
• No point in
says nothing about
treating genetic effects of novel
disorders environmental
experience

15. Heritable ≠ untreatable
• Because something is heritable does
NOT mean it is immutable
• Consider diabetes – large genetic
contribution to risk, but we do not
assume all diabetics must die!
• We may need to introduce new
environmental factors (e.g. insulin
treatment) outside range of normal
experience
• In case of SLI, may need to devise
specific interventions that circumvent or
compensate for genetically-based
problems
15

16. 'If a child has had bad teaching in mathematics, it is accepted that the
resulting deficiency can be remedied by extra good teaching the
following year. But any suggestion that the child's mathematical
deficiency might have a genetic origin is likely to be greeted with
something approaching despair: if it is in the genes "it is written", it is
"determined" and nothing can be done about it: you might as well give
up attempting to teach the child mathematics. This is pernicious
rubbish on an almost astrological scale
..... What did genes do to deserve their sinister juggernaut-like
reputation? Why do we not make a similar bogey out of, say, nursery
education or confirmation classes? Why are genes thought to be so
much more fixed and inescapable in their effects than television, nuns,
or books?"
Richard Dawkins, The extended phenotype. 1982. Oxford: OUP.