Autism is a devastating neurodevelopmental condition whose biological basis is still poorly understood. Furthermore, there are no laboratory or radiological tests available to aid in diagnosis, and although early behavioral intervention is considered effective in some cases, there are few proven treatments currently available. Autism has a striking genetic component with first degree relative risk estimated in some studies higher than 50. Therefore, defining the genes with variants contributing to autism risk would theoretically define the key molecular pathways involved. A number of genome-wide linkage scans and association studies performed in the last decade have begun to show promise by identifying a few overlapping regions of interest, but, no clear autism gene has been isolated and confirmed in multiple populations. In Iceland we have recruited most of confirmed autism cases in Iceland and used the genealogy database to connect many of these cases into the extended families. In preliminary analyses, suggestive loci have been found, most of which overlap with previously reported suggestive loci in autism scans, including those from a large subset of the AGRE/UCLA cohort, which consists of mostly nuclear multiplex autism pedigrees. Both the Decode group and the UCLA group have been attempting to increase the power of their respective cohorts by increasing the number of affecteds in their studies through broadening of the autism- related phenotyping to include quantitative measures of autism-related impaired social interaction, using the Social Responsiveness Scale (SRS). The use of this scale also allows for a QTL analysis that may further increase the power to find significant linkage, and takes advantage of the critical dimension of social deficits as a core feature of autism spectrum disorders in genetic studies for the first time. Genome-wide linkage scans in the ACRE and Decode populations have revealed a number of suggestive loci for autism or autism-related endophenotypes. Several of the loci with highest statistical support identified in ACRE and ICELAND cohorts overlap with each other and with loci from other populations, including an AGRE locus enhanced by QTL analysis based on SRS data. We believe that collaborative efforts to isolate genes from the strongest overlapping loci provides an efficient way to leverage these already recruited and genotyped patient cohorts. This grant proposal leverages both of these large cohorts that have already been genotyped in initial genome scans. We propose to phenotype additional relatives both in Iceland and the US, and analyze the US and Decode cohorts in parallel, performing the same multipoint QTL analysis, followed by fine mapping and narrowing regions of shared linkage. We plan to focus on the isolation of genes within loci that are supported in both populations.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Developmental Brain Disorders Study Section (DBD)
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Senthil, Geetha
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Decode Genetics, Ehf
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Lowe, Jennifer K; Werling, Donna M; Constantino, John N et al. (2015) Social responsiveness, an autism endophenotype: genomewide significant linkage to two regions on chromosome 8. Am J Psychiatry 172:266-75
Kong, Augustine; Frigge, Michael L; Masson, Gisli et al. (2012) Rate of de novo mutations and the importance of father's age to disease risk. Nature 488:471-5
Jacquemont, Sébastien; Reymond, Alexandre; Zufferey, Flore et al. (2011) Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus. Nature 478:97-102
Ingason, Andrés; Kirov, George; Giegling, Ina et al. (2011) Maternally derived microduplications at 15q11-q13: implication of imprinted genes in psychotic illness. Am J Psychiatry 168:408-17
Curran, Sarah; Bolton, Patrick; Rozsnyai, Kinga et al. (2011) No association between a common single nucleotide polymorphism, rs4141463, in the MACROD2 gene and autism spectrum disorder. Am J Med Genet B Neuropsychiatr Genet 156B:633-9
Moreno-De-Luca, Daniel; SGENE Consortium; Mulle, Jennifer G et al. (2010) Deletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizophrenia. Am J Hum Genet 87:618-30
Kallio, Suvi P; Jakkula, Eveliina; Purcell, Shaun et al. (2009) Use of a genetic isolate to identify rare disease variants: C7 on 5p associated with MS. Hum Mol Genet 18:1670-83
Stefansson, Hreinn; Rujescu, Dan; Cichon, Sven et al. (2008) Large recurrent microdeletions associated with schizophrenia. Nature 455:232-6