Joni A. Turunen

Analysis of four neuroligin genes as candidates for autism.

Neuroligins are cell-adhesion molecules located at the postsynaptic side of the synapse. Neuroligins interact with β-neurexins and this interaction is involved in the formation of functional synapses. Mutations in two X-linked neuroligin genes, NLGN3 and NLGN4, have recently been implicated in pathogenesis of autism. The neuroligin gene family consists of five members (NLGN1 at 3q26, NLGN2 at 17p13, NLGN3 at Xq13, NLGN4 at Xp22, and NLGN4Y at Yq11), of which NLGN1 and NLGN3 are located within the best loci observed in our previous genome-wide scan for autism in the Finnish sample. Here, we report a detailed molecular genetic analysis of NLGN1, NLGN3, NLGN4, and NLNG4Y in the Finnish autism sample. Mutation analysis of 30 probands selected from families producing linkage evidence for Xq13 and/or 3q26 loci revealed several polymorphisms, but none of these seemed to be functional. Family-based association analysis in 100 families with autism spectrum disorders yielded only modest associations at NLGN1 (rs1488545, P=0.002), NLGN3 (DXS7132, P=0.014), and NLGN4 (DXS996, P=0.031). We conclude that neuroligin mutations most probably represent rare causes of autism and that it is unlikely that the allelic variants in these genes would be major risk factors for autism.

RHD Maternal-Fetal Genotype Incompatibility Increases Schizophrenia Susceptibility

Fetal events and obstetric complications are associated with schizophrenia. Here we report the results of a family-based candidate-gene study that assesses the role of maternal-fetal genotype incompatibility at the RHD locus in schizophrenia. We adapted the case-parent-trio log-linear modeling approach to test for RHD maternal-fetal genotype incompatibility and to distinguish this effect from a high-risk allele at or near the RHD locus and from a direct maternal effect alone. Eighty-eight patient-parent trios, 72 patient-mother pairs, and 21 patient-father pairs were genotyped at the RHD locus. Of the 181 patients, 62% were male and 81% were second born or later. Only three patients were born after prophylaxis against maternal isoimmunization had become common practice. There was significant evidence for an RHD maternal-fetal genotype incompatibility, and the incompatibility parameter was estimated at 2.6. There was no evidence to support linkage/association with schizophrenia at or near the RHD locus nor any evidence to support the role of maternal genotype effect alone. Our results replicate previous findings that implicate the RHD locus in schizophrenia, and the candidate-gene design of this study allows the elimination of alternative explanations for the role of this locus in disease. Thus, the present study provides increasing evidence that the RHD locus increases schizophrenia risk through a maternal-fetal genotype incompatibility mechanism that increases risk of an adverse prenatal environment (e.g., Rh incompatibility) rather than through linkage/association with the disorder, linkage disequilibrium with an unknown nearby susceptibility locus, or a direct maternal effect alone. This is the first candidate-gene study to explicitly test for and provide evidence of a maternal-fetal genotype incompatibility mechanism in schizophrenia.

Latent Autoimmune Diabetes in Adults Differs Genetically From Classical Type 1 Diabetes Diagnosed After the Age of 35 Years

OBJECTIVE We studied differences between patients with latent autoimmune diabetes in adults (LADA), type 2 diabetes, and classical type 1 diabetes diagnosed after age 35 years. RESEARCH DESIGN AND METHODS Polymorphisms in HLA-DQB1, INS, PTPN22, and CTLA4 were genotyped in patients with LADA (n = 213), type 1 diabetes diagnosed at >35 years of age (T1D>35y; n = 257) or <20 years of age (T1D<20y; n = 158), and type 2 diabetes. RESULTS Although patients with LADA had an increased frequency of HLA-DQB1 and PTPN22 risk genotypes and alleles compared with type 2 diabetic subjects, the frequency was significantly lower compared with T1D>35y patients. Genotype frequencies, measures of insulin secretion, and metabolic traits within LADA differed according to GAD antibody (GADA) quartiles, but even the highest quartile differed from type 1 diabetes. Having two or more risk genotypes was associated with lower C-peptide concentrations in LADA. CONCLUSIONS LADA patients differed genetically and phenotypically from both T1D>35y and type 2 diabetic patients in a manner dependent on GADA levels.

Mitochondrial aspartate/glutamate carrier SLC25A12 gene is associated with autism.

Two single nucleotide polymorphisms (SNP) within Mitochondrial Aspartate/Glutamate Carrier SLC25A12 gene have recently shown to be strongly associated with autism. Here, we attempted to replicate this finding in two separate Finnish samples with autism spectrum disorders. Family‐based association analysis of two SNPs, rs2056202 and rs2292813, previously shown to be associated with autism was performed in two samples with different phenotypic characteristics. The samples included 97 families with strictly defined autism and 29 extended families with Asperger syndrome (AS). We detected association at rs2292813 (FBAT, P=0.0018) in the Finnish autism sample. In, addition other family‐based analysis methods supported this finding. By contrast, analysis of the AS sample yielded no evidence for association. This study shows further support that genetic variants within SLC25A12 gene contribute to the etiology of autism.

Mixture Model Clustering of Phenotype Features Reveals Evidence for Association of DTNBP1 to a Specific Subtype of Schizophrenia

BACKGROUND While DTNBP1, DISC1, and NRG1 have been extensively studied as candidate genes of schizophrenia, results remain inconclusive. Possible explanations for this are that the genes might be relevant only to certain subtypes of the disease and/or only in certain populations. METHODS We performed unsupervised clustering of individuals from Finnish schizophrenia families, based on extensive clinical and neuropsychological data, including Structured Clinical Interview for DSM-IV (SCID) information. Families with at least one affected member with DSM-IV diagnosis of a schizophrenia spectrum psychosis were included in a register-based ascertainment. Final sample consisted of 904 individuals from 288 families. We then used the cluster phenotypes in a genetic association study of candidate genes. RESULTS A robust three-class clustering of individuals emerged: 1) psychotic disorder with mood symptoms (n = 172), 2) core schizophrenia (n = 223), and 3) absence of psychotic disorder (n = 509). One third of the individuals diagnosed with schizophrenia were assigned to cluster 1. These individuals had fewer negative and positive psychotic symptoms and cognitive deficits but more depressive symptoms than individuals in cluster 2. There was a significant association of cluster 2 cases with the DTNBP1 gene, while the DISC1 gene indicated a significant association with schizophrenia spectrum disorders based on the DSM-IV criteria. CONCLUSIONS In the Finnish population, DTNBP1 gene is associated with a schizophrenia phenotype characterized by prominent negative symptoms, generalized cognitive impairment, and few mood symptoms. Identification of genes and pathways related to schizophrenia necessitates novel definitions of disease phenotypes associated more directly with underlying biology.

Association analysis of the AIRE and insulin genes in Finnish type 1 diabetic patients

Mutations in the autoimmune regulator (AIRE) gene cause a recessive Mendelian disorder autoimmune polyendocrinopathy syndrome type 1 (APS-1 or autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy). APS-1 patients develop multiorgan autoimmune diseases including type 1 diabetes (prevalence 12%). The AIRE protein controls the central tolerance induction in the thymus by regulating the expression levels of tissue-specific peripheral antigens, such as insulin. We hypothesized that the insulin gene (INS) polymorphisms together with the AIRE variations may predispose individuals to diabetes. The role of the AIRE gene was tested both independently and on the condition of the INS risk genotype in the Finnish type 1 diabetes sample. A total of 733 type 1 diabetic cases and 735 age- and sex-matched healthy controls were used in the analysis. Five common single nucleotide polymorphisms (SNPs) in the AIRE gene were selected from the public database (dbSNP). The −23HphI polymorphism was used as a surrogate marker for the INS gene promoter repeat. The five genotyped SNPs in the AIRE gene showed no evidence of association with type 1 diabetes. As expected, the INS gene polymorphism −23HphI was significantly associated with susceptibility to type 1 diabetes (P=6.8×10−12, χ2 test). When the subclass of patients carrying the homozygote genotype of the INS gene was used in the analysis, the AIRE polymorphisms showed no association with the disease. In conclusion, the AIRE gene does not seem to contribute to disease susceptibility in Finnish type 1 diabetic patients, whereas the insulin gene represents a notable risk factor for disease in this population.

RHD maternal-fetal genotype incompatibility and schizophrenia: extending the MFG test to include multiple siblings and birth order.

Rh incompatibility disease (ie Rh hemolytic disease of the fetus and newborn) has been implicated as a risk factor for schizophrenia. Here, we extend the maternal–fetal genotype incompatibility (MFG) test used in an earlier case–parent trio study that found significant evidence for an increased risk of schizophrenia in RHD MFG-incompatible children. We modify the MFG test for case–parent trios to include any number of siblings. This modified test enables us to use more of the available data from the earlier study. The increased sample size not only gives us greater power to test for MFG incompatibility but it also enables us to model the impact of previous RHD MFG-incompatible pregnancies on the relative risk of RHD MFG incompatibility in later-born siblings. This modeling is important, because RHD MFG incompatibility is a proxy for Rh incompatibility disease, and the risk of Rh incompatibility disease increases with the number of previous RHD MFG-incompatible pregnancies. The best-fitting models are consistent with the hypothesized effect that previous incompatible pregnancies increase the risk of schizophrenia due to RHD MFG incompatibility. There was significant evidence that the relative risk of schizophrenia in the second- and later-born RHD MFG-incompatible children is 1.7, consistent with earlier estimates. Our extension of the MFG test has general application to family-based studies of maternal-genotype and MFG interaction effects.

Linkage and linkage disequilibrium scan for autism loci in an extended pedigree from Finland

Population isolates, such as Finland, have proved beneficial in mapping rare causative genetic variants due to a limited number of founders resulting in reduced genetic heterogeneity and extensive linkage disequilibrium (LD). We have here used this special opportunity to identify rare alleles in autism by genealogically tracing 20 autism families into one extended pedigree with verified genealogical links reaching back to the 17th century. In this unique pedigree, we performed a dense microsatellite marker genome-wide scan of linkage and LD and followed initial findings with extensive fine-mapping. We identified a putative autism susceptibility locus at 19p13.3 and obtained further evidence for previously identified loci at 1q23 and 15q11-q13. Most promising candidate genes were TLE2 and TLE6 clustered at 19p13 and ATP1A2 at 1q23.

Association of AKT1 With Verbal Learning, Verbal Memory, and Regional Cortical Gray Matter Density in Twins

AKT1, encoding the protein kinase B, has been associated with the genetic etiology of schizophrenia and bipolar disorder. However, minuscule data exist on the role of different alleles of AKT1 in measurable quantitative endophenotypes, such as cognitive abilities and neuroanatomical features, showing deviations in schizophrenia and bipolar disorder. We evaluated the contribution of AKT1 to quantitative cognitive traits and 3D high‐resolution neuroanatomical images in a Finnish twin sample consisting of 298 twins: 61 pairs with schizophrenia (8 concordant), 31 pairs with bipolar disorder (5 concordant) and 65 control pairs matched for age, sex and demographics. An AKT1 allele defined by the SNP rs1130214 located in the UTR of the gene revealed association with cognitive traits related to verbal learning and memory (P = 0.0005 for a composite index). This association was further fortified by a higher degree of resemblance of verbal memory capacity in pairs sharing the rs1130214 genotype compared to pairs not sharing the genotype. Furthermore, the same allele was also associated with decreased gray matter density in medial and dorsolateral prefrontal cortex (P < 0.05). Our findings support the role of AKT1 in the genetic background of cognitive and anatomical features, known to be affected by psychotic disorders. The established association of the same allelic variant of AKT1 with both cognitive and neuroanatomical aberrations could suggest that AKT1 exerts its effect on verbal learning and memory via neural networks involving prefrontal cortex.

Leisure-Time Physical Activity Is Associated With the Metabolic Syndrome in Type 1 Diabetes Effect of the PPARγ Pro12Ala polymorphism: the FinnDiane Study

The metabolic syndrome varies in prevalence among different populations. A common feature, however, is a steep increase in prevalence along with a decrease in glucose tolerance (1–2). We have shown that 39% of adult type 1 diabetic patients have the metabolic syndrome (3), and similar data were recently reported from Italy (4). However, whether the metabolic syndrome observed in type 1 diabetes is the same as in nondiabetic and type 2 diabetic patients is unclear. Both lifestyle (5–8) and hereditary factors (9) seem to be involved in the development of the metabolic syndrome in nondiabetic and type 2 diabetic subjects. The PPARγ (peroxisome proliferator-activated receptor γ) Pro12Ala polymorphism has been associated with type 2 diabetes, the Ala allele being associated with a lower risk (10), and with the metabolic syndrome in some (11–12) but not all (13) studies. However, whether lifestyle or genetic factors also play a role in the development and treatment of the metabolic syndrome in patients with type 1 diabetes is unknown. Therefore, to further study the metabolic syndrome in type 1 diabetes, we investigated whether physical activity and/or the PPARγ Pro12Ala polymorphism are associated with metabolic syndrome in patients with type 1 diabetes in the Finnish Diabetic Nephropathy (FinnDiane) …