Linda Brzustowicz Professor Rutgers University Department of Genetics Life Sciences Building. Room 231 145 Bevier Road Piscataway. NJ 08854-8095 (732) 445-3331 FAX - 1636 brzustowicz@biology.rutgers.edu

Human genetic disorders

Our laboratory uses the techniques of molecular and statistical genetics to approach clinically relevant problems in neuroscience. with the ultimate goals of understanding gene function in both the pathologic and normal states. Our primary current focus is on three complex behavioral disorders: schizophrenia. autism and specific language impairment.

One main focus of our laboratory is on the genetics of schizophrenia. In collaboration with Dr. Anne Bassett. at the University of Toronto. we have conducted a genome-wide genetic linkage study of schizophrenia in a set of moderately large. extended families from eastern Canada (see Brzustowicz et al. Science 2000). and have identified a major schizophrenia susceptibility locus on chromosome 1q21-22. with a multipoint lod score of 6.50 (p<0.0002). In addition. the same set of families produced significant evidence of linkage to a second locus on chromosome 13q32 (see also Brzustowicz et al. AJHG 1999). as well as suggestive linkage findings to several additional loci. While these results were obtained using traditional diagnoses. our group also has an interest in the utility of alternative phenotypes for linkage analysis. Using one measure. the Positive and Negative Syndrome Scale (PANSS). we have detected a significant linkage of the severity of positive symptoms of schizophrenia to chromosome 6. which did not produce a significant linkage finding with traditional diagnoses (see Brzustowicz et al. AJHG 1997). We are now conducting fine genetic mapping. linkage disequilibrium analysis. and mutation screening of candidate genes from the various linked loci. In addition to our Canadian sample. we are also using samples from the NIMH Human Genetics Initiative. housed here at Rutgers. for these studies.

22q Deletion Syndrome (22qDS; also known as velocardiofacial syndrome) is a deletion syndrome of chromosome 22q11.2 characterized by cleft palate. cardiac anomalies. mild dysmorphic features. hypernasal speech. and learning disabilities. The extent of the deletion is variable. with most individuals deleted for a common 3 Mb region. but with a number of other specific deletions reported. The endpoints of the deletions appear to be defined by low copy repeat sequences on this region of chromosome 22. Approximately 25% of adults with 22qDS have schizophrenia. While the extent of the deletion in adult subjects with 22qDS does not appear to be the primary determinant of who will develop schizophrenia. we are searching for evidence of interaction of the chromosome 22 deletion with schizophrenia susceptibility loci elsewhere in the genome.

The other main focus of our laboratory is autism and language impairment. With Dr. Paula Tallal at Rutgers-Newark, we study a form of language impairment that is associated with an underlying inability to process rapidly presented stimuli. We have recently published a genome scan of Specific Language Impairment (SLI). and have identified a significant linkage finding on chromosome 13q21 (see Bartlett et al 2002). with several other suggestive loci on other chromosomes. This SLI locus is at the same position as a susceptibility locus for autism (see and Bartlett et al 2003). and we have expanded our studies to include the genetics of autism. We are currently launching a project to collect a new sample of families ascertained for both autism and a history of language impairment in non-autistic family members. and will be conducting a genome scan on these samples. In addition. we are currently conducting genetic association studies of autism using samples from the AGRE and NIMH Human Genetics Initiative collections.

Selected Publications

Brzustowicz LM. (2008) NOS1AP in schizophrenia. Curr Psychiatry Rep. 10(2):158-63.

Saviouk V, Moreau MP, Tereshchenko IV, Brzustowicz LM. (2007) Association of synapsin 2 with schizophrenia in families of Northern European ancestry. Schizophr Res. 96(1-3):100-11.

Brzustowicz LM. (2007) Size matters: the unexpected challenge of detecting linkage in large cohorts. Am J Psychiatry. 164(2):192-4.

Widom CS, Brzustowicz LM. (2006) MAOA and the "cycle of violence:" childhood abuse and neglect, MAOA genotype, and risk for violent and antisocial behavior. Biol Psychiatry. 60(7):684-9.

Talkowski ME. Seltman H. Bassett AS. Brzustowicz LM. Chen X. Chowdari KV. Collier DA. Cordeiro Q. Corvin AP. Deshpande SN. Egan MF. Gill M. Kendler KS. Kirov G. Heston LL. Levitt P. Lewis DA. Li T. Mirnics K. Morris DW. Norton N. O'donovan MC. Owen MJ. Richard C. Semwal P. Sobell JL. St Clair D. Straub RE. Thelma BK. Vallada H. Weinberger DR. Williams NM. Wood J. Zhang F. Devlin B. Nimgaonkar VL. (2006) Evaluation of a susceptibility gene for Schizophrenia: Genotype based meta-analysis of RGS4 polymorphisms from thirteen independent samples. Biol Psychiatry. 60(2):152-62.

Benayed R. Gharani N. Rossman I. Mancuso V. Lazar G. Kamdar S. Bruse SE. Tischfield S. Smith BJ. Zimmerman RA. Dicicco-Bloom E. Brzustowicz LM. Millonig JH. (2005) Support for the homeobox transcription factor gene ENGRAILED 2 as an autism spectrum disorder susceptibility locus. Am J Hum Genet. 77(5):851-68.

Xu B. Wratten N. Charych EI. Buyske S. Firestein BL. Brzustowicz LM. (2005) Increased expression in dorsolateral prefrontal cortex of CAPON in schizophrenia and bipolar disorder. PLoS Med. 2(10):e263.

Bartlett CW. Gharani N. Millonig JH. Brzustowicz LM. (2005) Three autism candidate genes: a synthesis of human genetic analysis with other disciplines. Int J Dev Neurosci. 23(2-3):221-34.

Wassink TH. Brzustowicz LM. Bartlett CW. Szatmari P. (2004) The search for autism disease genes. Ment Retard Dev Disabil Res Rev. 10(4):272-83.

Bartlett CW. Flax JF. Logue MW. Smith BJ. Vieland VJ. Tallal P. Brzustowicz LM. (2004) Examination of potential overlap in autism and language loci on chromosomes 2. 7. and 13 in two independent samples ascertained for specific language impairment. Hum Hered. 57(1):10-20.

Brzustowicz LM. Simone J. Mohseni P. Hayter JE. Hodgkinson KA. Chow EW. Bassett AS. (2004) Linkage disequilibrium mapping of schizophrenia susceptibility to the CAPON region of chromosome 1q22. Am J Hum Genet. 74(5):1057-63.

Flax JF. Realpe-Bonilla T. Hirsch LS. Brzustowicz LM. Bartlett CW. Tallal P. (2003) Specific language impairment in families: Evidence for co-occurrence with reading impairments. Journal of Speech. Language. and Hearing Research 46:530-543.

Bartlett CW. Flax J. Logue M. Vieland VJ. Bassett AS. Tallal P. Brzustowicz LM. (2002) A major susceptibility locus for specific language impairment is located on 13q21. American Journal of Human Genetics 71:45-55.

Brzustowicz LM. Hayter J. Hodgkinson KA. Chow EWC. Bassett AS. (2002) Fine mapping of the schizophrenia susceptibility locus on Chromosome 1q22. Human Heredity 54:199-209.

Tallal P. Hirsch LS. Realpe-Bonilla T. Miller S. Brzustowicz LM. Bartlett C. Flax JF. (2001) Familial aggregation in specific language impairment. Journal of Speech. Language. and Hearing Research 44:1172-1182.

Brzustowicz LM. Hodgkinson K. Chow EWC. Honer WG. and Bassett AS. (2000) Location of a major susceptibility locus for familial schizophrenia on Chromosome 1q21-22. Science 288(5466):678-682.