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1.  Influence of ZNF804a on Brain Structure Volumes and Symptom Severity in Individuals With Schizophrenia 
Archives of general psychiatry  2012;69(9):10.1001/archgenpsychiatry.2011.2116.
The single-nucleotide polymorphism rs1344706 in the gene ZNF804a has been associated with schizophrenia and with quantitative phenotypic features, including brain structure volume and the core symptoms of schizophrenia.
To evaluate associations of rs1344706 with brain structure and the core symptoms of schizophrenia.
Case-control analysis of covariance.
University-based research hospital.
Volunteer sample of 335 individuals with schizophrenia spectrum disorders (306 with core schizophrenia) and 198 healthy volunteers.
Main Outcome Measures
Cerebral cortical gray matter and white matter (WM) volumes (total and frontal, parietal, temporal, and occipital lobes), lateral ventricular cerebrospinal fluid volume, and symptom severity from the Scale for the Assessment of Negative Symptoms and the Scale for the Assessment of Positive Symptoms divided into 3 domains: psychotic, negative, and disorganized.
The rs1344706 genotype produced significant main effects on total, frontal, and parietal lobe WM volumes (F =3.98, P=.02; F =4.95, P=.007; and F =3.08, P =.05, respectively). In the schizophrenia group, rs1344706 produced significant simple effects on total (F =3.93, P=.02) and frontal WM volumes (F =7.16, P < .001) and on psychotic symptom severity (F =6.07, P=.003); the pattern of effects was concordant with risk allele carriers having larger volumes and more severe symptoms of disease than nonrisk homozygotes. In the healthy volunteer group, risk allele homozygotes had increased total WM volume compared with nonrisk allele carriers (F =4.61, P=.03), replicating a previously reported association.
A growing body of evidence suggests that the risk allele of rs1347706 is associated with a distinctive set of phenotypic features in healthy volunteers and individuals with schizophrenia. Our study supports this assertion by finding that specific genotypes of the polymorphism are associated with brain structure volumes in individuals with schizophrenia and healthy volunteers and with symptom severity in schizophrenia.
PMCID: PMC3852666  PMID: 22945618
2.  PRICKLE1 Interaction with SYNAPSIN I Reveals a Role in Autism Spectrum Disorders 
PLoS ONE  2013;8(12):e80737.
The frequent comorbidity of Autism Spectrum Disorders (ASDs) with epilepsy suggests a shared underlying genetic susceptibility; several genes, when mutated, can contribute to both disorders. Recently, PRICKLE1 missense mutations were found to segregate with ASD. However, the mechanism by which mutations in this gene might contribute to ASD is unknown. To elucidate the role of PRICKLE1 in ASDs, we carried out studies in Prickle1+/− mice and Drosophila, yeast, and neuronal cell lines. We show that mice with Prickle1 mutations exhibit ASD-like behaviors. To find proteins that interact with PRICKLE1 in the central nervous system, we performed a yeast two-hybrid screen with a human brain cDNA library and isolated a peptide with homology to SYNAPSIN I (SYN1), a protein involved in synaptogenesis, synaptic vesicle formation, and regulation of neurotransmitter release. Endogenous Prickle1 and Syn1 co-localize in neurons and physically interact via the SYN1 region mutated in ASD and epilepsy. Finally, a mutation in PRICKLE1 disrupts its ability to increase the size of dense-core vesicles in PC12 cells. Taken together, these findings suggest PRICKLE1 mutations contribute to ASD by disrupting the interaction with SYN1 and regulation of synaptic vesicles.
PMCID: PMC3849077  PMID: 24312498
3.  Genome-wide analysis of copy number variants in age-related macular degeneration 
Human genetics  2010;129(1):91-100.
Age-related macular degeneration (AMD) is a complex genetic disease, with many loci demonstrating appreciable attributable disease risk. Despite significant progress toward understanding the genetic and environmental etiology of AMD, identification of additional risk factors is necessary to fully appreciate and treat AMD pathology. In this study, we investigated copy number variants (CNVs) as potential AMD risk variants in a cohort of 400 AMD patients and 500 AMD-free controls ascertained at the University of Iowa. We used three publicly available copy number programs to analyze signal intensity data from Affymetrix® GeneChip SNP Microarrays. CNVs were ranked based on prevalence in the disease cohort and absence from the control group; high interest CNVs were subsequently confirmed by qPCR. While we did not observe a single-locus “risk CNV” that could account for a major fraction of AMD, we identified several rare and overlapping CNVs containing or flanking compelling candidate genes such as NPHP1 and EFEMP1. These and other candidate genes highlighted by this study deserve further scrutiny as sources of genetic risk for AMD.
PMCID: PMC3613489  PMID: 20981449
4.  Copy Number Variations and Primary Open-Angle Glaucoma 
This study has identified rare and recurrent deletions and duplications in POAG patients in the first large-scale, whole-genome study of structural variation performed in a sample of POAG patients and POAG-free subjects.
This study sought to investigate the role of rare copy number variation (CNV) in age-related disorders of blindness, with a focus on primary open-angle glaucoma (POAG). Data are reported from a whole-genome copy number screen in a large cohort of 400 individuals with POAG and 500 age-matched glaucoma-free subjects.
DNA samples from patients and controls were tested for CNVs using a combination of two microarray platforms. The signal intensity data generated from these arrays were then analyzed with multiple CNV detection programs including CNAG version 2.0, PennCNV, and dChip.
A total of 11 validated CNVs were identified as recurrent in the POAG set and absent in the age-matched control set. This set included CNVs on 5q23.1 (DMXL1, DTWD2), 20p12 (PAK7), 12q14 (C12orf56, XPOT, TBK1, and RASSF3), 12p13.33 (TULP3), and 10q34.21 (PAX2), among others. The CNVs presented here are exceedingly rare and are not found in the Database of Genomic Variants. Moreover, expression data from ocular tissue support the role of these CNV-implicated genes in vision-related processes. In addition, CNV locations of DMXL1 and PAK7 overlap previously identified linkage signals for glaucoma on 5p23.1 and 20p12, respectively.
The data are consistent with the hypothesis that rare CNV plays a role in the development of POAG.
PMCID: PMC3207715  PMID: 21310917
5.  G72 Influences Longitudinal Change in Frontal Lobe Volume in Schizophrenia 
Schizophrenia is a neurodevelopmental psychiatric disorder characterized by a variety of structural brain abnormalities that appear to progress across the course of illness. Schizophrenia also is highly heritable, and one gene that has emerged as a possible susceptibility factor is G72. G72 influences brain development and activity by an as-yet unclear mechanism, and multiple studies have reported associations between G72 and schizophrenia. We were interested in linking these domains of investigation by determining whether G72 also influences the rate of longitudinal structural brain changes in individuals with schizophrenia. As part of the Iowa Longitudinal Study of Recent Onset Psychoses, we genotyped four G72 polymorphisms previously associated with schizophrenia in 110 subjects with schizophrenia or schizoaffective disorder from whom we had obtained two brain MRI scans an average of three years apart. The four polymorphisms captured three haplotypes, one of which was strongly associated with an increased rate of frontal lobe volume decrement. This same haplotype was also associated with more severe psychotic symptoms at the time of the second scan. These data thus suggest that variation in G72 modulates the progressive brain changes that characterize schizophrenia.
PMCID: PMC2908546  PMID: 19760675
DAOA; MRI; schizophrenia; frontal lobe; psychosis
6.  Autism genome-wide copy number variation reveals ubiquitin and neuronal genes 
Nature  2009;459(7246):569-573.
Autism spectrum disorders (ASDs) are childhood neurodevelopmental disorders with complex genetic origins1–4. Previous studies focusing on candidate genes or genomic regions have identified several copy number variations (CNVs) that are associated with an increased risk of ASDs5–9. Here we present the results from a whole-genome CNV study on a cohort of 859 ASD cases and 1,409 healthy children of European ancestry who were genotyped with ~550,000 single nucleotide polymorphism markers, in an attempt to comprehensively identify CNVs conferring susceptibility to ASDs. Positive findings were evaluated in an independent cohort of 1,336 ASD cases and 1,110 controls of European ancestry. Besides previously reported ASD candidate genes, such as NRXN1 (ref. 10) and CNTN4 (refs 11, 12), several new susceptibility genes encoding neuronal cell-adhesion molecules, including NLGN1 and ASTN2, were enriched with CNVs in ASD cases compared to controls (P = 9.5 × 10−3). Furthermore, CNVs within or surrounding genes involved in the ubiquitin pathways, including UBE3A, PARK2, RFWD2 and FBXO40, were affected by CNVs not observed in controls (P = 3.3 × 10−3). We also identified duplications 55 kilobases upstream of complementary DNA AK123120 (P = 3.6 × 10−6). Although these variants may be individually rare, they target genes involved in neuronal cell-adhesion or ubiquitin degradation, indicating that these two important gene networks expressed within the central nervous system may contribute to the genetic susceptibility of ASD.
PMCID: PMC2925224  PMID: 19404257

Results 1-6 (6)