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1.  QTL replication and targeted association highlight the nerve growth factor gene for nonverbal communication deficits in autism spectrum disorders 
Molecular psychiatry  2011;18(2):226-235.
Autism Spectrum Disorder (ASD) has a heterogeneous etiology that is genetically complex. It is defined by deficits in communication and social skills and the presence of restricted and repetitive behaviors. Genetic analyses of heritable quantitative traits that correlate with ASD may reduce heterogeneity. With this in mind, deficits in nonverbal communication (NVC) were quantified based on items from the Autism Diagnostic Interview Revised. Our previous analysis of 228 families from the Autism Genetics Research Exchange (AGRE) repository reported 5 potential quantitative trait loci (QTL). Here we report an NVC QTL replication study in an independent sample of 213 AGRE families. One QTL was replicated (P < 0.0004). It was investigated using a targeted-association analysis of 476 haplotype blocks with 708 AGRE families using the Family Based Association Test (FBAT). Blocks in two QTL genes were associated with NVC with a P-value of 0.001. Three associated haplotype blocks were intronic to the Nerve Growth Factor (NGF) gene (P= 0.001, 0.001, 0.002), and one was intronic to KCND3 (P= 0.001). Individual haplotypes within the associated blocks drove the associations (0.003, 0.0004 and 0.0002) for NGF and 0.0001 for KCND3. Using the same methods, these genes were tested for association with NVC in an independent sample of 1517 families from an Autism Genome Project (AGP). NVC was associated with a haplotype in an adjacent NGF block (P= 0.0005) and one 46 kb away from the associated block in KCND3 (0.008). These analyses illustrate the value of QTL and targeted association studies for genetically complex disorders such as ASD. NGF is a promising risk gene for NVC deficits.
PMCID: PMC3586745  PMID: 22105621
autism spectrum disorders; GWAS; nerve growth factor; nonverbal communication; QTL
2.  GWA study data mining and independent replication identify cardiomyopathy-associated 5 (CMYA5) as a risk gene for schizophrenia 
Molecular psychiatry  2010;16(11):1117-1129.
We conducted data-mining analyses using the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and molecular genetics of schizophrenia genome-wide association study supported by the genetic association information network (MGS-GAIN) schizophrenia data sets and performed bioinformatic prioritization for all the markers with P-values ≤0.05 in both data sets. In this process, we found that in the CMYA5 gene, there were two non-synonymous markers, rs3828611 and rs10043986, showing nominal significance in both the CATIE and MGS-GAIN samples. In a combined analysis of both the CATIE and MGS-GAIN samples, rs4704591 was identified as the most significant marker in the gene. Linkage disequilibrium analyses indicated that these markers were in low LD (3 828 611–rs10043986, r2 = 0.008; rs10043986–rs4704591, r2 = 0.204). In addition, CMYA5 was reported to be physically interacting with the DTNBP1 gene, a promising candidate for schizophrenia, suggesting that CMYA5 may be involved in the same biological pathway and process. On the basis of this information, we performed replication studies for these three single-nucleotide polymorphisms. The rs3828611 was found to have conflicting results in our Irish samples and was dropped out without further investigation. The other two markers were verified in 23 other independent data sets. In a meta-analysis of all 23 replication samples (family samples, 912 families with 4160 subjects; case–control samples, 11 380 cases and 15 021 controls), we found that both markers are significantly associated with schizophrenia (rs10043986, odds ratio (OR) = 1.11, 95% confidence interval (CI) = 1.04–1.18, P = 8.2 × 10−4 and rs4704591, OR = 1.07, 95% CI = 1.03–1.11, P = 3.0 × 10−4). The results were also significant for the 22 Caucasian replication samples (rs10043986, OR = 1.11, 95% CI = 1.03–1.17, P = 0.0026 and rs4704591, OR = 1.07, 95% CI = 1.02–1.11, P = 0.0015). Furthermore, haplotype conditioned analyses indicated that the association signals observed at these two markers are independent. On the basis of these results, we concluded that CMYA5 is associated with schizophrenia and further investigation of the gene is warranted.
PMCID: PMC3443634  PMID: 20838396
association study; cardiomyopathy; GWA data mining; meta-analysis; schizophrenia>
4.  Expanding the range of ZNF804A variants conferring risk of psychosis 
Molecular psychiatry  2010;16(1):59-66.
A trio of genome-wide association studies recently reported sequence variants at three loci to be significantly associated with schizophrenia. No sequence polymorphism had been unequivocally (P<5×10−8) associated with schizophrenia earlier. However, one variant, rs1344706[T], had come very close. This polymorphism, located in an intron of ZNF804A, was reported to associate with schizophrenia with a P-value of 1.6×10−7, and with psychosis (schizophrenia plus bipolar disorder) with a P-value of 1.0×10−8. In this study, using 5164 schizophrenia cases and 20 709 controls, we replicated the association with schizophrenia (odds ratio OR= 1.08, P= 0.0029) and, by adding bipolar disorder patients, we also confirmed the association with psychosis (added N= 609, OR= 1.09, P= 0.00065). Furthermore, as it has been proposed that variants such as rs1344706[T]—common and with low relative risk—may also serve to identify regions harboring less common, higher-risk susceptibility alleles, we searched ZNF804A for large copy number variants (CNVs) in 4235 psychosis patients, 1173 patients with other psychiatric disorders and 39 481 controls. We identified two CNVs including at least part of ZNF804A in psychosis patients and no ZNF804A CNVs in controls (P= 0.013 for association with psychosis). In addition, we found a ZNF804A CNV in an anxiety patient (P = 0.0016 for association with the larger set of psychiatric disorders).
PMCID: PMC3242031  PMID: 20048749
schizophrenia; bipolar disorder; ZNF804A; CNV; association
5.  Family-based association analysis implicates IL-4 in susceptibility to Kawasaki disease 
Genes and immunity  2005;6(5):438-444.
Several compelling lines of evidence suggest an important influence of genetic variation in susceptibility to Kawasaki disease (KD), an acute vasculitis that causes coronary artery aneurysms in children. We performed a family-based genotyping study to test for association between KD and 58 genes involved in cardiovascular disease and inflammation. By analysis of a cohort of 209 KD trios using the transmission disequilibrium test, we documented the asymmetric transmission of five alleles including the interleukin-4 (IL-4) C(−589)T allele (P = 0.03). Asymmetric transmission of the IL-4 C(−589)T was replicated in a second, independent cohort of 60 trios (P = 0.05, combined P = 0.002). Haplotypes of alleles in IL-4, colony-stimulating factor 2 (CSF2), IL-13, and transcription factor 7 (TCF7), all located in the interleukin gene cluster on 5q31, were also asymmetrically transmitted. The reported associations of KD with atopic dermatitis and allergy, elevated serum IgE levels, eosinophilia, and increased circulating numbers of monocyte/macrophages expressing the low-affinity IgE receptor (FCεR2) may be related to effects of IL-4. Thus, the largest family-based genotyping study of KD patients to date suggests that genetic variation in the IL-4 gene, or regions linked to IL-4, plays an important role in KD pathogenesis and disease susceptibility.
PMCID: PMC2911125  PMID: 15889128
pediatrics; vasculitis; coronary artery aneurysm; Th2 immune response; transmission disequilibrium test; polymorphism

Results 1-5 (5)