Genetic influences on specific language impairment

Dorothy Bishop

University of Oxford

SLI runs in families

Rates of language/learning difficulties higher in relatives of those with SLI, compared with controls of similar background

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10

20

30

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50

Neils,

1986

Bishop,

1986

Tallal,

1989

Tomblin,

1989

% aff ected

relatives

SLI control

Dizygotic or non-identical(DZ) twins: For genes that vary between people, have identical version for 50%

Twin Study Method

Monozygotic (MZ) twins: genetically identical

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.

Study of twins growing up together

SSLI low language speech therapy mental handicap

DZ: n = 27 MZ: n = 63

Diagnosis in co-twins of probands with specific speech/language impairment (SSLI)

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.

Yellow area shows the proportion of twin 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.

KE family

Black = Speech/language impairment

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.

A family tree that suggested there was a ‘gene for SLI’

Grandparents

Parents

Children

If you have an affected parent,you have 50% chance of having SLI

Fisher, S. E. (2005). Dissection of molecular mechanisms underlying speech and language disorders. Applied Psycholinguistics, 26, 111-128.

• 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

Finding the gene

• 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”

But KE family - not typical SLI

Complex multifactorialdisorders

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

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Many common medical conditionsbehave this way, e.g. allergies, asthma,high blood pressure, diabetes

Low

High

Several genes, each with a small effect,

combine with environmental risks

to influenceobserved behaviour

acrossthe whole range

Idea of underlying continuum

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Tracking down genes associated with SLI

Gene 1: CMIP Gene 2: ATPTC2

• 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 differentfrom FOXP2.‘Risk’ alleles common in general populationand have smalleffect size

11Newbury, D., et al. (2009). CMIP and ATP2C2 modulate phonological short-term memory in language impairment. American Journal of Human Genetics, 85, 264-272

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.

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

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See:http://wiringthebrain.blogspot.co.uk/2012/06/probabilistic-inheritance-and.html

Genetics: common misconceptions

• Genes are the only thing that matter

• No point in treating genetic disorders

NO! even in MZ twins, find different severity

NO! genetic analysis says nothing about effects of novel environmental experience

• 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

Heritable ≠ untreatable

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'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.