Language disorders in children what can they tell us about genes and brains
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Language disorders in children: What can they tell us about genes and brains?. Dorothy Bishop University of Oxford. Specific language impairment (SLI). Diagnosed in children when language does not follow normal developmental course

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Language disorders in children what can they tell us about genes and brains

Language disorders in children:What can they tell us about genes and brains?

Dorothy Bishop

University of Oxford


Specific language impairment sli

Specific language impairment (SLI)

  • Diagnosed in children when language does not follow normal developmental course

  • Problems with language structure (phonology and syntax) common

  • Not due to hearing loss, physical abnormality, acquired brain damage

  • Normal development in other areas


What causes sli

What causes SLI?


Language disorders in children what can they tell us about genes and brains

http://news.bbc.co.uk/1/hi/education/2638889.stm

Thursday, 9 January, 2003, 11:15 GMT

Daily grunt parents hold children back

Not enough talking going on

Parents who do little more than grunt at their children every day are damaging their language development, a literacy expert has said.

Alan Wells, director of the Basic Skills Agency, says parents no longer talk to their children and instead just let them sit in front of the television or computer for hours.


Evidence against poor language environment as cause of sli

Evidence against poor language environment as cause of SLI

  • Most children develop adequate language despite very variable levels of language input from parents

    • E.g. different cultures

    • Children in exceptional circumstances, including hearing children of deaf parents

    • Twin studies: dizygotic twins growing up in same environment can be very different


Is brain damage implicated

Is brain damage implicated?

  • Early idea of “continuum of reproductive casualty” - i.e. brain damage incurred around time of birth might lead to learning disabilities

Intraventricular

hemorrhage : a

common

feature of

prematurity


Evidence against brain damage as cause of sli

Evidence against brain damage as cause of SLI

  • No obvious signs of neurological impairment in most cases of SLI

  • No excess of perinatal problems in SLI

  • Children who do have focal lesions affecting the language areas don’t develop SLI - see Basser 1962!


Genetics

Genetics


Sli family aggregation

SLI: Family aggregation

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


Language disorders in children what can they tell us about genes and brains

Twin Study Method

MZ twins: genetically identical

DZ twins: share 50% of polymorphic genes

Question:

Is concordance for disorder higher in MZ than in DZ twins?


Twin studies of sli

Twin studies of SLI

Probandwise

concordance:

same-sex twins

MZDZ

Lewis & Thompson, 1992 .86.48

Bishop et al, 1995 .70.46

Tomblin & Buckwalter, 1998 .96.69

Hayiou-Thomas et al, 2005 .36 .33

Bishop & Hayiou-Thomas, 2008 .88 .35

(same sample, criteria of SALT contact)


Conclude

Conclude……..

Evidence for substantial genetic influence on SLI

But lots of questions remain, e.g.:

  • Can SLI be caused by a single gene?

  • Is SLI a single condition, or are there etiologically distinct subtypes?

  • What (if anything) does this say about evolution of language?


Single gene disorder ke family

Single gene disorder: KE family

Hurst et al, 1990; Gopnik, 1990;

Vargha-Khadem et al, 1995


Language disorders in children what can they tell us about genes and brains

Nature, October 4th 2001

A forkhead-domain gene is mutated

in a severe speech and language disorder

Lai, C. S., Fisher, S. E., Hurst, J. A.,

Vargha-Khadem,F., & Monaco, A.

  • FOXP2: gene on chromosome 7q31

  • Single base mutation in affected individuals

  • No allelic variation in people with normal language


Language disorders in children what can they tell us about genes and brains

Nature, August 22nd 2002

Molecular evolution of FOXP2, a gene

involved in speech and language

Enard, W., Przeworski, M., Fisher, S. E., Lai, C. S. L.

Wiebe, V., Kitano, T., Monaco, A. P., Paabo, S.

  • FOXP2 differs in man and mouse in only 3 amino acid positions

  • FoxP2 differs in man vs. chimp, gorilla, rhesus macaque in 2 amino acid positions

  • i. e. 2/3 differences between human/mouse occurred on human lineage after separation from chimpanzee


Is foxp2 a grammar gene

Is FOXP2 a 'grammar gene'?

No!

  • FOXP2 is a transcription factor: regulates expression of many other genes, and expressed in multiple organs

  • Affected members of KE family have problems beyond grammar

  • Abnormality of subcortical regions involved in motor control

(Watkins et al, 2002)


Language disorders in children what can they tell us about genes and brains

Nevertheless,affected members poor at syntactic tasks, even

when no speech is required, e.g.

The elephant pushing the boy is big


How to characterise foxp2

How to characterise FOXP2

  • A transcription factor that affects expression of many other genes, and is expressed in multiple organs

  • Human version of gene may be important for building brain areas involved in extracting hierarchical structure from linear input


Q1 can sli be caused by a single gene

Q1. Can SLI be caused by a single gene?

  • Yes, in case of FOXP2

  • But! This is the exception rather than the rule

  • No abnormality of FOXP2 seen in majority of cases of SLI

  • Pedigree analysis does not show straightforward pattern suggestive of single gene disorder


Sli as complex multifactorial disorder

SLI as complex multifactorialdisorder

  • Aggregates but does not segregate in families

  • Typical etiology for common disorders

    e.g. heart disease, diabetes


The quest for heritable phenotypes

The quest for heritable phenotypes

  • Need to move from clinical diagnosis to measures of underlying impairment


Some promising component skills

Some promising component skills

  • Auditory processing skills (e.g., Tallal)

  • Morphosyntax (e.g., Rice & Wexler)

  • Phonological short-term memory (e.g., Gathercole & Baddeley)


Children s nonword repetition test cnrep

Children’s Nonword Repetition Test (CNRep)

Gathercole and Baddeley, 1990

Child listens to spoken nonwords and repeats, e.g.

2 syllables: hampent

3 syllables: dopelate

4 syllables: confrantually

5 syllables: pristoractional


Nonword repetition

Nonword repetition

NB performance

near ceiling on

2 syllable nonwords

data from Bishop et al, 1996


Language disorders in children what can they tell us about genes and brains

Genetic analysis:

quantitative rather than categorical approach


Defries fulker df analysis

nonshared environment only

shared environment only

genes only

co-twin

co-twin

DeFries-Fulker (DF) analysis

DZ

proband

MZ

proband

-1

0

z-score


Nonword repetition test df analysis

Nonword Repetition Test: DF analysis

h2g = 1.17

(SE = .319)


Involvement of phonological stm in syntax learning

Involvement of phonological STM in syntax learning?

  • Baddeley et al (1998) notion of phonological loop as buffer to hold information while computing syntactic relations

  • Joanisse & Seidenberg (1998) problems that seem specific to grammar may be secondary consequences of phonological memory deficit

    To get beyond correlational evidence, can use twin method to test for common origins in different deficits


Language disorders in children what can they tell us about genes and brains

Twin Sample6 yr olds from community twin sample (TEDS), biased to include those with language difficulties

  • 65 MZ and 67 DZ pairs with ‘low language’ on basis of parental report at 4 yr

  • 37 MZ and 29 DZ control pairs (neither ‘low language’)

Bishop et al., 2006


Nonword repetition1

Nonword repetition

NB test not given to 19 children with unintelligible speech

Residual score: total correct on 3-, 4- and 5-syllable nonsense words predicted from the total of 2-syllable words: gives purer measure of memory


Nonword repetition heritability of extreme scores

Nonword repetition: heritability of extreme scores

h2g = .84

(95%CI = .58)


Language disorders in children what can they tell us about genes and brains

Rice-Wexler task:

test of grammatical morphology

“Here the boy is raking; now he is done.

Tell me what he did”.


Language disorders in children what can they tell us about genes and brains

Here’s a farmer.

Tell me what a

farmer does.


N children inflecting verbs

N children inflecting verbs

Mann Whitney; z = 5.75, p < .001

Bishop et al., 2006


Rice wexler task heritability of extreme scores 93 inflected

Rice-Wexler task: heritability of extreme scores (< 93% inflected)

h2g = .68

(95%CI = .59)


Nonword repetition probands cotwin z scores on verbs

Nonword repetition probands; cotwin z-scores on verbs

h2g.xy = .32

(95%CI = .71)

co-twin verb

proband phonSTM

co-twin verb

proband phonSTM


Language disorders in children what can they tell us about genes and brains

Genetic risk 2

Genetic risk 1

Conclusions from twin study

Morphosyntax

deficit

Phonological

STM deficit

MZ twins more similar to each other than DZ, but only within-trait

MZ twins more similar to each other than DZ

phonological

STM deficit

phonological

STM deficit


Are there separate subtypes of sli

Are there separate subtypes of SLI?

  • Poor phonological STM

  • Poor grammatical morphology


Phenotypic overlap phonological stm verb morphology deficits

Phenotypic overlap: phonological STM / verb morphology deficits

phi = .29, p < .001


Language disorders in children what can they tell us about genes and brains

children with co-occurring

deficits are most likely

to be identified with SLI

phonological STM deficit

morphosyntax deficit

Suggests language is a strongly canalised function:

will develop despite variation in underlying cognitive bases


Q2 is sli a single condition or are there heritable subtypes

Q2. Is SLI a single condition, or are there heritable subtypes?

Neither seems true!

  • Notion of disorder that arises only when there is more than one underlying deficit

  • Predicts relatives will show deficit without necessarily showing disorder

  • Predict genetic variants will be risk factors rather than act as single causes


Study of parents

Study of parents

Barry, J. G., Yasin, I., & Bishop, D. V. M. (2007). Heritable risk factors associated with language impairments. Genes, Brain and Behavior, 6, 66-76.


Mean language literacy scores in parents

Mean language/literacy scores in parents

NB significant differences maintained when self-report LI excluded


Sli consortium molecular genetic studies

SLI consortium: molecular genetic studies

  • Have found 3 genetic variants that are associated with nonword repetition in SLI samples

  • Two genes on chromosome 16 act additively; other gene is downstream target of FOXP2

  • Poor performance on verb morphology linked to site on chromosome 19


Genes associated with nonword repetition deficits

Genes associated with nonword repetition deficits

Very different from FOXP2

  • 'Risk' variants are common in the general population

  • Associated with a drop in nonword repetition score, but of moderate magnitude

    Two genes on chromosome 16

Gene 1

Gene 2

figures from Dianne Newbury


Implications

Implications

  • Supports notion that language involves multiple cognitive processes

  • Syntactic deficits not reducible to more basic cognitive process (at least, not to those measured here)

  • Search for single cause explanations of SLI may be doomed - language is resilient enough to survive one deficit


Thanks to

Thanks to:

Caroline Adams & Courtenay Norbury

6 yr old twin testing project

Robert Plomin

Twins Early Development Study

Mabel Rice

making prepublication test materials available

Dianne Newbury, Tony Monaco, Simon Fisher

making prepublication genetic results available


Language disorders in children what can they tell us about genes and brains

Dorothy Bishop

Oxford Study of Children’s

Communication Impairments,

Department of Experimental

Psychology,

South Parks Road,

Oxford,

OX1 3UD,

England.

[email protected]

References available on: http://www.psy.ox.ac.uk/oscci/


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