Genetics of Language & Language Disorders

1. Genetics of Language & Language Disorders Karin Stromswold* Dept. of Psychology & Center for Cognitive Science Rutgers University - New Brunswick • Portions of this work were supported by • Johnson & Johnson Foundation • John Merck Foundation • Charles & Johanna Busch Biomedical Research Grant • Bamford-Lahey Children’s Foundation • •National Science Foundation (BCS-9875168, BCS-0042561,BCS-0124095) • * Correspondence may be sent to karin@ruccs.rutgers.edu

2. Key Questions • Do genetic factors affect people’s ability to acquire and use language? • Do these factors affect 'normal' people’s linguistic abilities or just those with language disorders? • Do language-specific genes exist? • Are genetic factors involved in all aspects of language? • Are the same genetic factors involved in all aspects of language? • How do genes/environment interact?

3. Innateness Hypothesis & Heritability • Typical evidence: Universal, learnable, modular • Genetic evidence: If innate cognitive predisposition or neural structures enable us to use/acquire language, they must be encoded in our DNA • Why we might fail to find evidence for language heritability Heritability = amount of individual variation due to genetic factors • The Innateness Hypothesis is wrong • Linguistically-speaking, (normal) people are genetically identical Chomsky (1980): Language is like number of fingers Lieberman (1984): Language is like height

4. Innateness Hypothesis & Heritability • Individual differences may exist • Acquisition rate for vocabulary (e.g., Goldfield & Reznick, 1990), morphology (e.g., deVilliers & deVilliers, 1973), syntax (e.g., Stromswold 1990, 1995, Snyder & Stromswold 1997).…. • Adult linguistic proficiency: verbal fluency (e.g., Day, 1979), compound nouns (e.g., Gleitman & Gleitman, 1970), sentence processing (e.g., Corely & Corley, 1995; Bever et al., 1989), second language acquisition (e.g., Fillmore, 1979), grammaticality judgments (e.g., Ross, 1979; Nagatu, 1992; Cowart, 1994). • Caveat: Genetic factors could account for differences among abnormal populations but not normal populations • The case with number of fingers: genetic syndromes associated with too many/few fingers • (Contrast with heritability of finger length)

5. Methodology • The power of meta-analyses: • Increase statistical power • Methodological weaknesses of individual studies less worrisome • Searched PsycINFO, ERIC, & Medline databases for • language, linguistic, articul, speech, read or spellAND • hereditary, genetic, famil, twin, adoption, chromosom, linkage, pedigree, sex-ratio, segregation, aggregation, DNA, or RNA • Excluded language disorders that were acquired, progressive, syndromic, or secondary to hearing loss, mental retardation, psychiatric/neurological disorder etc.

6. Family Aggregation of Spoken Disorders • Do language disorders aggregate (cluster) in families? • Yes: Meta-analyses of 18 studies revealed • SLI probands are more likely to have a positive family history 46% (range 24-78%) vs. 18% (range 3-46%) • SLI probands have more impaired relatives than do controls 28% (range 20-42%) vs. 9% (range 3-19%) • Caveat: Difficult to separate the role of genes vs. environment (Deviant Linguistic Environment Hypothesis)

7. DLEH Predictions are not Borne Out • Language impairments sometimes skip generations • Most severely impaired children don’t come from families with highest incidence of impairment • Parents who speak normally (but have history of language delay) are more likely to have language-impaired children • Even in families with very high impairment rates, some family members are normal • In most families, some siblings are impaired and others are not • No relationship between birth order and probability of impairment • Concordance is no greater between primary care provider and child & other first degree relatives • Language-impaired children don’t always have the same impairment as their relatives

8. Pedigree Studies: Modes of Transmission • Autosomal Dominant (AD): Most probands will have 1 impaired parent, and half of siblings will be impaired • Autosomal Recessive (AR): Most probands will have 2 unaffected parents, and one quarter of siblings will be affected • X-linked Recessive (XLR): Impaired males have 1 bad gene, impaired females have two bad genes. Thus, the M:F is n:n2 (where n is the frequency of the disordered allelle) • Most genetic language disorders aren’t SML. Review of lit shows • One-third of probands have 1 affected parent: Genetic heterogeneity or AD with high rate of spontaneous mutation, or incomplete penetrance or expressivity • One-quarter of probands have 2 affected parents: High assortative mating, very high incidence of language disorders, SML models are wrong • One-third of siblings are impaired: Either AR or genetically heterogeneous • Sex ratios generally between 2:1 to 3:1. Even most extreme only 6:1 Not XLR

9. Colorado Adoption Project (CAP) • Rationale: If genes are important for a trait, adopted children’s abilities will resemble their biological relatives’abilities. If environment is important, adopted children will resemble their adopted relatives. • Design: Large (N>300) longitudinal study that compares adopted and nonadopted children’s skills with those of their biological and adopted parents and siblings. • Language Disorders (Felsenfeld & Plomin, 1997): 156 children at age 7 • Positive biological family history was the best predictor of language disorders • 25% of children with + biological family history were impaired (9% with + adopted FH) • Sibling comparisons at age 7 (Cardon et al., 1992): • Vocab + verbal fluency h = .90 (IQ-related = .46, Language-specific = .83) • Fluency only h = .33 (IQ-related = .54, Language-specific = .20) • Vocab only h = .47 (IQ-related = .69, Language-specific = .00)

10. CAP Parent-Child Comparison(Plomin et al., 1997) Verbal Abilities Spatial Abilities Processing Speed Recognition Memory

11. CAP Conclusions • Heritable factors affect verbal abilities more than other types of abilities • The influence of genetic factors becomes more apparent with age • Specific-to-language factors are only seen at age 7 (but this may be because overall IQ was used). • Caveats about adoption studies: • All studies from a single group of children (what if not representative) • Verbal assortative mating was greater for adoptive parents than biological parents: This probably lowered heritability estimates • Selective adoptive placement was not a problem (low correlation between adoptive and biological mothers’ verbal skills)

12. Twin Study Rationale • Rationale: Identical (monozygotic, MZ) and non-identical (dizygotic, DZ) twin pairs share the same environment, but MZ cotwins share 100% of their DNA, whereas DZ twins share 50% of their DNA • Therefore: If MZ cotwins are more similar linguistically than DZ twins, this suggests that genetics plays a role in language. • Can quantify the relative role of genetics and environment by measuring how much more similar MZ twins are than DZ twins.

13. Concordance Rates for Twin Pairs • Are concordance rates for MZ > DZ twins? Number of Impaired Individuals in Concordant Pairs Total Number of Impaired Individuals • Two types of meta-analyses • Mean rates: Treat each studies’ MZ & DZ concordance rates as data points, and use sign- and t-tests to determine if there is a significant difference. • Overall rates: Pool data from all studies and calculate overall concordance rates. Use Z-scores to test if MZ-DZ rates are different

14. Twin Correlational Analyses • Are MZ twins’ test scores more highly correlated than DZ twins? • Phenotypic variance =variation for a trait in a population • Heritable factors: Falconer’s h2 = 2[rMZ - rDZ] • Common environment factors: c2 = rMZ - h2 • Non-shared environmental factors: e2 = 1 - rMZ • Unweighted meta-analysis: rMZ and rDZ are data points • Weighted meta-analysis : Weighted mean Fisher’s z’s for MZ and DZ twins were calculated and compared using Z-scores

15. MZ Concordance Rates are Higher • Spoken language disorders: 5 studies (266 MZ, 161 DZ pairs) • Mean: 84% for MZ, 52% for DZ, p < .0001 • Overall: 84% for MZ, 48% for DZ, p < .0001 • Written language disorders: 5 studies (212 MZ, 199 DZ pairs) • Mean: 76% for MZ, 41% for DZ, p < .01 • Overall: 75% for MZ, 43% for DZ, p < .0001 • Combined spoken/written disorders (478 MZ, 360 DZ pairs) : • Mean: 80% for MZ, 46% for DZ, p < .0001 • Overall: 80% for MZ, 46% for DZ, p < .0001 • But why aren’t MZ concordance rates 100%? Three possibilities: • MZ twins aren’t identical genetically and/or environmentally • Expressivity of language disorders is incomplete • Failure to diagnose language disorders in some MZ cotwins • [DZ pair-wise concordance rate (26%) is similar to non-twin siblings (30%)]

16. Spoken Language Disorders

17. Written Language Disorders

18. SLI Twins’ Test Performance • Bishop et al (1995): 63 MZ, 27 DZ twin pairs • Articulation: Falconer’s h2 = 1.82 • Phonological STM: DF h2g = 1.25 • Receptive vocabulary: DF h2g = 1.35 • Morphosyntax: Wechsler h2g = 1.10, CELF h2g = .56, TROG h2g = 1.09 • (But when nonverbal IQ partialled out, no significant genetic effects) • Bishop et al (1999): • 27 MZ, 21 DZ: Pure tone sequence repetition DF h2g = .11 • 25 MZ, 22 DZ: Nonword repetition DF h2g = 1.17 • Tomblin & Buckwalter’s (1998) data minus triplets (58 twins): • Falconer’s h2 = .66, p = .05 • Bivariate heritability for nonverbal IQ & language = .21 • Genetic correlation, RG = .01 (ie., different genetic factors influence verbal & nonverbal disability)

19. TEDS Twins’ Test Performance • TEDS study: Largepopulation-based, parent report twin study • Dale et al (1998): Analyzed data for twins with the smallest vocabularies (bottom 5%tile, 135 twin pairs). DF h2g = .73 (vs. h2 = .25 for all TEDS twins) • Eley et al. (1999): DF h2g greater for TED twins with small vocabularies than twins with normal vocabularies. • Eley et al. (2001): genetic continuity is greater for small vocab probands than other proband groups • Purcell et al. (2001): Are the genetic factors specific to vocabulary? • When probands were selected based on small vocabularies, RG for low verbal & nonverbal scores = 1.0 (i.e., the genetic factors that cause 2 years olds to have small vocabularies are the same as those that cause them to have nonverbal delays.) • When probands were selected based on poor nonverbal scores, the vocabulary-nonverbal RG = .36 • [Why the asymmetry: Differences in homogeneity of the samples? Problems with the measure? Directionality of effect?]

20. Colorado Twin Study of Reading Disability • Olson et al (1989): Genetic factors played a large role for phonological reading (DF h2g = .93) but not orthographic reading (DF h2g = .-.16). • Light et al. (1998). DF h2g for phonological reading = .52; overall reading = .70 • Castles et al (1999): Genetic factors account for twice as much of the variance in phonological dyslexics as orthographic dyslexic (67% vs. 31%) • Gayan & Olson (1999): contra Castles et al. (1999) argue thatheritable factors play a significant role in all types of dyslexia. • Olson et al. (1999) & Wadsworth et al. (2000):genetic factors play a greater role in reading disability among children with high IQs than low IQs • Light et al. (1998): RG for overall reading/math = .36 (60% due to genetic factors common with IQ and 20% due to genetic factors common to phonological reading)

21. Summary: Twin Language Disorders • Some language disorders are genetically based (25-100%) • Genetic factors probably affect the linguistic abilities of disordered populations more than the general public (75% vs. 25%) • Genetic language disorders seem to impact different aspects of language, but less is known about phonology, morphology & syntax • Unknown if the same genetic factors cause different types of language disorders (and even if they do, what would this mean?) • Unclear if the genetic factors identified are specific to language • The few existing studies have conflicting results, possibly reflecting aspects of language assessed, methods of assessing etc.

22. Normal Twin Vocabulary Studies • Overall: 8 studies with 1577 MZ, 1389 DZ twins • Unweighted mean rMZ = .81, rDZ = .57, Falconer’s h2 = .48 (p = .002) • Weighted mean rMZ = .93, rDZ = .76, Falconer’s h2 = .33 (p < .0001) • Early: 3 studies with 1247 MZ, 1152 DZ twins 18-24 months old • Unweighted mean rMZ = .91, rDZ = .78, Falconer’s h2 = .26 (p = .08) • Weighted mean rMZ = .95, rDZ = .80, Falconer’s h2 = .29 (p < .0001) • Late: 5 studies with 330 MZ, 237 DZ twins 3-13 years old • Unweighted mean rMZ = .75, rDZ = .44, Falconer’s h2 = .62 (p = .001) • Weighted mean rMZ = .71, rDZ = .45, Falconer’s h2 = .53 (p = .02) • Role of genes increases with age (2 long. studies & meta-analysis) • Unclear whether genes are specific to language (1 study yes, 1 study no, 1 longitudinal study yielded different results at different ages) • Different genes affect normal & impaired twins’ vocabulary: • Bottom 5%tile TEDS: complete genetic overlap for vocab & nonverbal skills. • For all TEDS twins, vocabulary-specific genetic factors exist

23. Normal Twin Vocabulary Studies

24. Normal Twin Phonology/Articulation • Phoneme Discrimation: 21 pairs of 2-3 year olds (Fischer 1973) • rMZ = .64, rDZ = .53, Falconer’s h2 = .22 (p > .10) • Phonemic Awareness: 126 pairs of 6-7 year olds (Hohnen & Stevenson 1999) • Weighted mean rMZ = .90, rDZ = .56, Falconer’s h2 = .68 (p < .001) • Age 6: 29% IQ-related genetic factors, 23% vocab/morphosyntax, 9% phonology • Age 7: 18% IQ-related genetic factors, 67% vocab/morphosyntax-related • Phonological STM: 100 pairs of 7-13 year old twins (Bishop et al. 1999) • Heritable factors do not affect the ability to repeat sequences of pure tones • Heritable factors do affect the ability to repeat nonsense words (h2 = .71, p = .01) • Articulation: 180 pairs of 3-8 yrs (Matheny & Bruggemann ‘73, Mather & Black ‘84) • Weighted mean rMZ = .93, rDZ = .79, Falconer’s h2 = .26 (p = .03)

25. Normal Twin Phonology & Articulation

26. Normal Twin Morphosyntax • 12 twin studies of children between 20 months & 12 years. • Diversity of methods used and aspects of morphosyntax assessed precludes combining data from these studies, but … • rMZ significantly greater than rDZ for all measures in 5 studies, 2/3s of measures in 1 study, and 1/2 of measures in 2 studies. In 4 studies, MZ-DZ differences were not significant in majority of measures • rMZ > rDZ in 33 of 36 measures, p < .0001 • Mean rMZ > rDZ for each of 12 studies, p < .0001 • Significant differences were more common in larger studies and in studies that used ‘cleaner’ measures of morphosyntax • Do language-specific genes exist? • Munsinger & Douglass (1976): MZ-DZ difference significant even when nonverbal IQ partialled out • Hohnen & Stevenson (1999): Syntax-specific genes account for 20-30% • Dale et al. (1999): Genetic factors are specific to language but not syntax (however, parent-report syntax measure is worrisome) • No evidence that influence of genetics increases with age

27. Normal Twin Morphosyntax

28. Normal Twin Written Language • Reading: 5 studies with 745 twin pairs • Weighted mean rMZ = .86, rDZ = .66, Falconer’s h2 = .45, p = .002 • Hohnen & Stevenson (1999): Some genetic factors are specific to language but not reading (20-30%), with a modest amount specific to reading (20-30%). Genetic factors common to IQ have only a modest effect (10%), and genetic factors specific to phonemic awareness have no effect on normal children’s reading (c.f., dyslexia findings) • Spelling: 2 studies with 246 twin pairs (Osborne et al, 1968; Stevenson et al, 1987) • Weighted mean rMZ = .78, rDZ = .48, Falconer’s h2 = .60, p = .002 • Stevenson et al. (1987): Heritabilty estimates are greater for IQ-adjusted scores than non-adjusted scores (.73 vs. .53)

29. Normal Twin Reading

30. Summary of Twin Results • Genetic factors play a greater role for language-impaired people (~1/2 -2/3) than “normals”(~1/4-1/2) • Genetic factors affect all aspects of language • Probable existence of some language-specific genes • Possible existence of some genes specific to different aspects of language

31. Potential Worries With Twin Studies • Gene/environment interactions & the generalizability of heritability estimates obtained from twins: • Twins have higher rates of impairments/delays than singletons • Twins have impoverished prenatal & postnatal environments • Environmental assumptions: • Prenatal: Do MZ and DZ twin pairs have the same prenatal environment? • Postnatal: Do MZ and DZ twin pairs have the same postnatal environment? • => Swedish Separated-at-Birth Twin Study (Pedersen et al 1994) yielded similar heritability estimates for reared apart twins as is found for reared together twins • Genetic assumptions: • Are MZ twins genetically identical? • Are DZ twins genetically equivalent to siblings?

32. Linkage Studies Background • Naming conventions • Humans have 22 pairs of autosomal & 2 sex (Y, X) chromosomes • Autosomal chromosomes are numbered from 1-22 by size (1 is largest) • Each chromosome has a constriction: short arm (p) long arm (q) • Thus, 15q21 refers to staining band 21 on long arm of chromosome 15 • Multiplex analyses: Compare DNA of affected and unaffected family members in highly affected SML transmission families. Do marker locus and trait locus assort independently or is there decreased recombination (indicating 2 loci are neighbors)? Logarithm of odds score > 3 indicates linkage. LOD of -2 indicates no linkage. Problem: multiplex analyses reveal genes that can cause SLI, but rarely do • Sibling pair analyses: Compare DNA of affected and unaffected siblings. If a trait locus is closely linked to a marker locus, similarity between siblings for the marker alleles should correspond with phenotypic similarity, regardless of the mode of transmission (i.e., works with non-SML disorders)

34. The KE Family KE family: Multiplex family with AD disorder that includes grammatical deficits (Gopnik 1990), oral dyspraxia (Fisher et al. 1998, Hurst et al. 1990), and low nonverbal IQ and nonverbal learning disorders (Vargha-Khadem et al. 1995)

35. 7q31 Loci for Spoken Impairments • Fisher et al. (1998): Disorder in KE family is linked to 7q31 • Tomblin et al. (1998): Linkage of SLI with 7q31 in a population-based study of second graders • Lai et al. (2000): The disorder is linked to 7q31.2 in affected KE family members and an unrelated person with a similar disorder • Lai et al (2001): All and only affected family KE members have an abnormal form of the FOXP2 gene. The gene codes for transcription factor, and is highly expressed in fetal tissue and its homologue is found in mouse cerebral cortex. • Enard et al. (2002) : The FOXP2 homologue in non-human primates (and mouse) differs from that of humans. • Genetic link between 7q31 and Tourette Syndrome and autism

36. Other Loci for Spoken Impairments • Froster et al. (1993): Family with 1p22 and 2q31 translocation associated with written & spoken impairments • Elcioglu et al. (1997): Isolated case of severe language delay but normal nonverbal abilities: Inverted duplication of 15q13->15q2. • Bartlett et al. (2000): 19 multiplex families with linkage near 4 dyslexia loci (1p36, 2p15, 6p21, 15q21). No linkage to 7q31 • Cholfin et al. (2000): Multiplex family with AD transmission, but no linkage to 7q31 • SLI consortium (2002): 98 siblings. 16q24 (nonword rep), 19q13 • Bartlett et al. (2002): 5 Canadian multiplex families: 13q21

37. Going from Loci to Genes • SLI: Lai et al. (2001): FOXP2 transcription factor gene. • Dyslexia: possible candidate genes • 1p34-p36: • 2p15-p16: phosphotase calcineuron (psychiatric disorders) • 6p21-p23: HLA (autoimmune), GABA-beta receptor 1 (CNS inhibitor), lyso-phospholipid coenzyme A acyl transferase (fatty acid and membrane phospholipid metabolism gene), human kinesin gene (C elegans mutant have behavioral disorders) …. • 6q13-16.2: • 15q21-q23: beta2-microglobin gene (autoimmune); neuronal tropomodulin 2 & 3 (a major binding protein to brain tropomyosin) • 11p15.5: dopamine D4 receptor gene

38. What we don’t know …. Phonology • Do genetic factors affect phonology (vs. articulation)? Stromswold & Ganger (in prep): analysis of monthly spontaneous speech samples (22-47 mo) from 8 sets of normal twins • Size of phonetic inventory is not more similar for MZ cotwins • Order of acquisition of phonemes is more similar for MZ cotwins • Accuracy rate is more similar for MZ cotwins • Syllable initial: 7.7% vs. 16.4% • Syllable final: 9.9% vs. 15.9% • Patterns of errors may be more similar for MZ cotwins • Substitution rates similar, but MZ cotwins more likely to make the same substitutions • MZ cotwins more likely to make the same classes of substitution errors (e.g., fronting, voicing errors, stopping) • Deletion rates more similar for MZ than DZ cotwins

39. What we don’t know …. Syntax • To what extent do genetic factors play a role in syntax? • Published syntax studies generally are small and/or use worrisome measures • To do large-scale studies, we need a syntax test that parents can administer • The Parent Assessment of Language (PAL) We’ve designed and are norming a series of parent-administered test for children ages 3 and above. Each year’s PAL tests children’s comprehension of syntactic constructions that children are mastering at that age (actives, passives, reflexive, pronouns, relative clauses,modals, subjunctives, subject and object control structures, etc.). • Longitudinal twin study using the PAL (current N = 120)

40. PAL Syntax Items (Picture-pointing) • Age 3 & Age 4 • 4 Full Actives: The bear licked the dog 4 Full Passives: The bear was licked by the dog • 2 Easy Reflexives: The bear licked himself 2 Easy Pronouns: The bear licked him • Age 5 & Age 6: • 1 Full Active: The bear was licking the dog 1 Truncated Active: The bear was licking • 3 Full Passives: The bear was licked by the dog 3 Truncated Passives: The bear was licked • 2 Easy Reflexives: The bear was licking himself 2 Easy Pronouns: The bear was licking him • Ages 7 & 8 • 1 Full Active: The bear was licking the dog 1 Truncated Active: The bear was licking • 3 Full Passives: The bear was licked by the dog 3 Truncated Passives: The bear was licked • 1 Easy Reflexives: The bear was licking himself 1 Med Reflexive: The dog's friend was licking himself • 1 Easy Pronoun: The bear was licking him 1 Med Pronoun: The dog's friend was licking him • Ages 9 & 10 • 1 Full Active: The bear was licking the dog 1 Truncated Active: The bear was licking • 3 Full Passives: The bear was licked by the dog 3 Truncated Passives: The bear was licked • 1 Med Refl.: The dog's friend was licking himself 1 Hard Refl: The friend of the dog was licking himself • 1 Med Pronoun: The dog's friend was licking him 1 Hard Pronoun: The friend of the dog was licking him • Age 11 and above All preceded by One of these two dogs is hot and followed by the query Which dog is hot? • 3 Active Right Branch RC: The bear was licking the dog who __ is hot. • 3 Active Center Embed RC: The dog who the bear was licking _ is hot. • 3 Passive Right Branch RC: The bear was licked by the dog who __ is hot • 3 Passive Center Embed RC: The dog who the bear was licked by __ is hot.

47. PAL Syntax: Yes/No/Maybe Task (Ages 9+) • Sally said “Shouldn’t you make the knot tight?” Did Sally think the knot should be tight? • Billy won’t go to the park unless John goes. Will Billy stay home? • Katie promised Lucy, who was thirsty, to buy juice. Did Lucy say she would buy juice? • Mary who is going to the party with Steve does not like to dance. Does Mary enjoy dancing? • Michael’s cat chased the mouse and ran away. Did Michael’s cat run away? • Jim thinks Tom is bad at sports. Is Tom bad at sports? • Maybe the band would have played last night if the drummer hadn’t quit. Did the band play last night? • The doctor who was looking for the nurse walked home from the hospital. Did the doctor walk home from the hospital?

48. What we don’t know …. Specificity • Do language-specific genes exist? • Need more, large studies that assess development in many different areas (not just cognitive abilities, but also fine motor, gross motor, oral motor, social etc.) • Do specific genes for different aspects of language exist? (e.g., syntax-specific, phonology-specific, lexicon-specific) • Need to assess multiple aspects of language in a large group of children • Data that we are collecting in our twin study: • PAL: assesses articulation, lexical access, reading/pre-reading, and syntax • ASQ: parent assessment of gross motor, fine motor, cognitive, language & social-emotional skills • Developmental milestones (gross motor, fine motor, cognitive, language, social) • Special educational/therapy services • Neuropsychological diagnoses

49. Sample PAL (Age 4) Articulation of onsets: List any sounds the child regularly says wrong, and give a typical mispronounced word Lexicon: Rapid naming (number of foods named in 30 seconds) Pre-reading: Capital letter identification. (Orthographic and phonologic word reading starting at age 6 PAL.) Syntax: Picture pointing comprehension task 4 actives (e.g., the dog licked the bear) 4 passives (e.g., the fox was tickled by the lion) 2 reflexives (e.g., the cat scratched himself) 2 pronouns (e.g., the monkey splashed him)

50. What we don’t know …Gene x Environment • Koeppen-Schomerus et al. (2000): Heritable factors play a negligible role in linguistic and cognitive abilities of very premature TEDS twins. • What is the relative importance of prenatal and postnatal environment? • We are comparing heritability estimates for twins with easy/hard prenatal courses • Gestational age • Birthweight • Birthweight percentile • Brain injuries • Short (discharged before or by due date ) vs. long hospital stays • Composite neonatal morbidity measure • We are comparing heritability estimates for twins with different postnatal environments (SES, therapeutic interventions, traditional vs. developmental NICUs) • Are there specific perinatal factors that place twins at risk (e.g., steroids, MgSO4, intrauterine infection, placental infarction, ventilation, TTTS, etc.)? • Quantifying the role of prenatal environment: we are comparing outcomes for MZ twins with very similar birth weights and very different birth weights (MZS -MZD ) and DZ twins with similar/different birth weights