autism susceptibility loci• figure 1. chromosomal regions with evidence of linkage in 10...
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AUTISM SUSCEPTIBILITY
LOCI
K30/K12 Meeting
Ana Isabel Alvarez Retuerto, PhD.
What is Autism?
• Early onset (3 yr, even 18 mth or 1 yr)
• Social & communicative impairments
• Repetitive & stereotype behaviors
• Not a distinct disorder but a spectrum(ASDs or PDD, Rett, Asperger, etc)
• Affectation mild-severe
• Other (Mental Retardat., Fra. X., Seizures,Tuberous Sclerosis, etc.)
Diagnosis
• Diagnostic and Statistical Manual for MentalDisorders (DSM-IV) and International Classif.Diseases (ICD10) (last 15 years)
• Autism Diagnostic Interview (ADI) (Le Couteur et al,
1989) or ADI-R (revised), Autism DiagnosticObservation Schedule (ADOS) (Lord C. et al, 2000).
• Other test (Vineland, Peabody Picture VocabularyTest-PPVT, Raven)
Epidemiology
• Rate of PDDs= 60/10,000 (rates of PDD-
NOS & Asperger vary widely w/ survey)
• Prevalence of Autism= 13/10,000
• Asperger Syndrome= 3/10,000
• Mean Male: Female ratio= 4:1• (Fombonne E. et al, 2005)(34 surveys, 14 countries, published
English)
Autism (Causes & Genetics)(1)
• Heritable complex disorder (Rutter, 2000; Folstein & Rosen-
Sheidley, 2001; Lamb et al, 2002).
• Concordance rate MZ twins 60-95%; DZ twins &
siblings 0% and 10% for autism and ASD (Bailey et
al 1995; Folstein & Rutter 1977; Folstein & Rutter 1988; Ritvo et al 1985;
Steffenburg et al 1989).
• Siblings recurrence risk for autism & ASD 2-4.5%(Chakrabarti & Fombonne 2001; Fombonne 2003; Yeargin-Allsopp et al
2003).
• ASD not a Simplex Mendelian Fashion.
Autism (Causes & Genetics)(2)
• Several loci (3-15) proposed (Pickles et al 1995;
Risch et al 1999).
• Clinical complexity & heterogeneity.
• Genetic heterogeneity (several genes in
different families).
• Environmental influences.
Autism/Genetics
• 5-10% show chromosomal abnormalities
– 15q duplication (1-3%)
– Fragile X (1-3%)
– Sex Chromosomes (1-3%)
• Most case complex genetics (3-15 loci proposed)
– Different genes or interactions might cause same
phenotype (multigenic). Several genes act together to
produce full phenotype (polygenic) and/or with
environment (multifactorial).
Susceptibility Loci Search
• 1) Find chromosomal region by linkage
analysis
• 2) Search gene/s or regions through
association studies.
Genome Scans
• 1) Genome-wide scans using microsatellite
markers.
• Many independent genome-scans
several chromosomal regions
no consistent replication of strong linkage
findings
overlap of some regions in these international
family scans.
Genomic Regions Found
• Figure 1. Chromosomal regions with evidence of linkage in 10 genome-wide scans for ASD susceptibility loci. If a dataset has been expanded and updated in subsequent studies, only the most recent publication has been considered.Results fromeach study are indicated by a letter, followed by ** if MLS>3.6, by * if MLS>2.2, and by 8 if MLS>1.A:AGRE[Yonan et al., 2003]; (a) AGRE2 [Cantor et al., 2005]; (B) [Buxbaum et al., 2001], (C) CLSA [Barrett et al., 1999];(D) Duke [Shao et al., 2002b]; (F) Finland [Auranen et al., 2002]; (I) IMGSAC [Lamb et al., 2005]; (M) [McCauley et al.,2005]; (P) PARIS [Philippe et al., 1999]; (S) Stanford [Risch et al., 1999].(Bacchelli et al 2006)
Overlapping Regions
• Chromosome 2q [IMGSAC 2001, Lamb et al 2005, Philippe et
al 1999, Buxbahum et al 2001, Shao et al 2002].
• Chromosome 7q, “AUTS1”, [Int’l Molecular Genetic
Study Autism Consortium, IMGSAC 1998, 99 fam, MLS=2.53][IMGSAC 2001; Lamb et al 2005, Barret et al 1999, Philippe etal 1999, Risch et al 1999, Liu et al 2001, Alarcon et al 2002 & 2005,Auranen et al 2002, Shao et al 2002, Moloy et al 2005, Shellenberg etal 2006].
• Chromosome 17q [IMGSAC 2001, Yonan et al 2003, Stone et
al 2004, Cantor et al 2005, Lamb et al 2005, McCauley et al 2005]
• Loci found & (# diff. studies): Chr.1p(3), 2q(4),3q(4), 4q(3), 6q(4), 7q(8), 10q(4), 13q(3), 16p(7)& 19p(4)
Collaborative Effort (1)
• Unraveling the pathophysiology of the disorder.
• Genetic contribution & interaction or risk withenvironmental factors.
• Understanding the process, prevention, treatment,interventions.
• FAMILIES PARTICIPATION.
• Difficult family environment & ethical issues.
Collaborative Effort (2)
• Autism Genetic Resource Exchange
(AGRE)(www.agre.org) & Cure Autism Now(www.cureautismnow.org)
• National Institute Mental Health NIMH Human
Genetics Repository. 830 (749 MPX families/4014
indiv (w/ DNA & clinical assesments)
• Molecular Cytogenetics and Karyotype (Dr. L Martin &
Dr. Ledbetter/ Emory Univ.)
• Genome Scans
Cytogenetics
• AGRE, abnormal karyotype=13/544 fam.
(2.38%); Fra.X Mut.= 17/751 fam. (2.26%)
Collaborative Effort
Genome Scans (1)• 1) Columbia Univ. (1a) [110 MPX fam, 335 markers].
Main findings: Broad Diag.: Chr. 5p & Xq. Narrow Diag.:Chr. 19q & Xq. Also 8q & 16p (p< 0.01). (1b) Follow-up156 fam (46more) Chr. 7q, 17q & X. (Liu et al 2001). (1c)345 Sib-pairs(235 new). 408 markers (73 new) Chr. 17q11,5p, 11p, 4q & 8q (p<0.01). (Yonan et al 2003). (1c/d) Chr17q11 (p<0.01), 148 sibships Male-only. (Stone et al2004).
• AGRE + Finnish families, [314 fam (288 AGRE + 26Finnish)], Chr. 1p12q25, 3p24-26, 4q21-31, 5p15-q12,6q14-21, 7q33-36, 8q22-24, 17p12-q21 & 19p13-q13(p<0.05). (Ylisaukko-oja T. et al 2006)
Collaborative Effort
Genome Scans (2)
• 2) CIDR scan, [109 sib-pairs, 400 markers], Chr17q21(p<0.01) MO. Formal replication (Cantor et al2005).
• 3) AGP (Autism Genome Project)(NAAR & NIH)(50centers USA+Europe) [1496 fam/7917 fam. members;~ 10,000 SNPs]. Sugg. Link. 11p12-13 & 15q23-25.3(Narrow Diag. FC: 5p15.33, 9p24.1 & 11p13-12,MO:5q12.3 & 9q33.3 (diff. Locat. From FC). Other:2q (FC), 7q modest link (MO). (AGP Consortium2007).
Endophenotypes/QTL (1)
– 1) QTL WORD, PHRASE, RSB: [152 MPX fam. 335 markers]. WORD
Chr7q35 (p=0.001) & chr11(p=0.013). PHRASE Chr10(p=0.018),
11(p=0.014) & 20 (p=0.011) (Alarcon et al 2002)
– 2) QTL WORD, PHRASE, RSB: [291(152+139 new) MPX fam. 408
markers]. WORD Chr3q (p<0.001) & 17q (p=0.002), chr.7q35. PHRASE
Chr17(p=0.013), chr.3(p=0.04) & chr.16 (p=0.019). RSB Chr.16
(p=0.006) (Alarcon et al 2005)
– 3) QTL Non-verbal Communication. [228 MPX fam., 408 markers].
Chr.1p13-q12(p=0.0001), chr.4q21-25(p=0.0008),chr.7q35(p=0.008),chr8q23-24(p=0.005) and 16p12-13 (p=0.001)( OSA) (Chen et al
2006).
Endophenotypes/QTL (2)
• 4) Linkage/Stratification fam. Lang. Delay [133 MPX
fam, 365 markers] Chr.2,4, 6,7,8 & 9(p<0.05).
Chr.1,10,12,15 & 19 (p<0.01)(WD or PD). (Spence et
al 2005)
• 5) Social Responsiveness Scale (SRS) QTL [99 MPX
fam 408 markers, teacher reported]. Chr.11 & 17
(p<0.01). Also MO (p<0.01) in chr. 11, 17 & chr, 4, 8
& 10 (p<0.01). (Duvall et al 2007)
Association Studies
• A) Illumina= 516 SNPs returned clean in 217 AGRE trios.
16 candidate genes assessed with dense SNP typing on chrs 7 and 17 (Stone et
al 2007). 5 neuroligin familiy members tested. No association found.
(www.agre.org)
• B) Perlegen= 12,500 SNPs typed on 1,000 individuals (333Trios) (MPX fam).
220 trios returned. Chr.5, 7 &17, 51 cand. genes neuronal migration, 31 genes
that escape X-inactivation. Candidate pathways also tested (neuronal migration
& synaptic plasticity). Several genes show association. Overrepresentation of
SNPs found (NRXN1, NRXN3, GABARB3).
• D) Illumina= (SNP Repl. Perlegen Results). 384 SNPs in 330 independent
trios. Analysis ongoing searching for replication of previous reported genes.
(CNTNAP2 QTL & Language Delay) .
• Gene profiling in autistic (Fra.X+Chr,15 dup) cell lines (Nishimura et al 2007)
Ongoing
• Focus on endophenotypes. (Word, Phrase,
RSB, Language impairment, SRS, Head
Circumference, Chr.15q+Fragile-X, etc).
• Infant sibs & Endophenotypes.
• Preparation of 3rd stage replication
(CNPNAP2) AGRE+ other cohorts.
• Imaging & Genetics.(CNTNAP2 & fMRI)
Acknowledgments
• UCLA• Daniel H. Geschwind
• Stanley F. Nelson
• Rita Cantor
• Maricela Alarcon
• Sarah Spence
• Jennifer Stone
• Jackie Duvall
• Gary Chen
• Naoko Kono
• Ake Lu
• AGRE & FAMILIES
• Emory University• Christa L. Martin
• David Ledbetter
• University of
Chicago• T. Conrad Gilliam
• Amanda L. Yonan
• NIH grants R01 MH 64547 and U54
MH068172 to Dr. Daniel H. Geschwind