Association study of nonsynonymous single nucleotide polymorphisms in schizophrenia.

Background: Genome-wide association studies using several hundred thousand anonymous markers present limited statistical power. Alternatively, association studies restricted to common nonsynonymous single nucleotide polymorphisms (nsSNPs) have the advantage of strongly reducing the multiple testing problem, while increasing the probability of testing functional single nucleotide polymorphisms (SNPs).

Methods: We performed a case-control association study of common nsSNPs in Galician (northwest Spain) samples using the Affymetrix GeneChip Human 20k cSNP Kit, followed by a replication study of the more promising results.

Partial support for ZNF804A genotype-dependent alterations in prefrontal connectivity.

Genome-wide association studies identified the single nucleotide polymorphism rs1344706 in ZNF804A as a common risk-variant for schizophrenia and bipolar disorder. Whereas the molecular function of ZNF804A is yet unclear, recent imaging genetics studies have started to characterize the neural systems architecture linking rs1344706 genotype to psychosis. Carring rs1344706 risk-alleles was associated with a decrease in functional connectivity within the dorsolateral prefrontal cortices (DLPFCs) as well as an increase in connectivity between the DLPFC and the hippocampal formation (HF) in the context of a working memory task.

Missing heritability in the tails of quantitative traits? A simulation study on the impact of slightly altered true genetic models.

Objective: Genome-wide association studies have identified robust associations between single nucleotide polymorphisms and complex traits. As the proportion of phenotypic variance explained is still limited for most of the traits, larger and larger meta-analyses are being conducted to detect additional associations. Here we investigate the impact of the study design and the underlying assumption about the true genetic effect in a bimodal mixture situation on the power to detect associations.

Common variants on 8p12 and 1q24.2 confer risk of schizophrenia.

Schizophrenia is a severe mental disorder affecting ∼1% of the world population, with heritability of up to 80%. To identify new common genetic risk factors, we performed a genome-wide association study (GWAS) in the Han Chinese population. The discovery sample set consisted of 3,750 individuals with schizophrenia and 6,468 healthy controls (1,578 cases and 1,592 controls from northern Han Chinese, 1,238 cases and 2,856 controls from central Han Chinese, and 934 cases and 2,020 controls from the southern Han Chinese).

Genome-wide pooling approach identifies SPATA5 as a new susceptibility locus for alopecia areata.

Alopecia areata (AA) is a common hair loss disorder, which is thought to be a tissue-specific autoimmune disease. Previous research has identified a few AA susceptibility genes, most of which are implicated in autoimmunity. To identify new genetic variants and further elucidate the genetic basis of AA, we performed a genome-wide association study using the strategy of pooled DNA genotyping (729 cases, 656 controls).

The role of variation at AβPP, PSEN1, PSEN2, and MAPT in late onset Alzheimer's disease.

Rare mutations in AβPP, PSEN1, and PSEN2 cause uncommon early onset forms of Alzheimer's disease (AD), and common variants in MAPT are associated with risk of other neurodegenerative disorders. We sought to establish whether common genetic variation in these genes confer risk to the common form of AD which occurs later in life (>65 years). We therefore tested single-nucleotide polymorphisms at these loci for association with late-onset AD (LOAD) in a large case-control sample consisting of 3,940 cases and 13,373 controls.

The impact of a Dysbindin schizophrenia susceptibility variant on fiber tract integrity in healthy individuals: a TBSS-based diffusion tensor imaging study.

Schizophrenia is a severe neuropsychiatric disorder with high heritability, though its exact etiopathogenesis is yet unknown. An increasing number of studies point to the importance of white matter anomalies in the pathophysiology of schizophrenia. While several studies have identified the impact of schizophrenia susceptibility gene variants on gray matter anatomy in both schizophrenia patients and healthy risk variant carriers, studies dealing with the impact of these gene variants on white matter integrity are still scarce.

Genome-wide association study in German patients with attention deficit/hyperactivity disorder.

The heritability of attention deficit hyperactivity disorder (ADHD) is approximately 0.8. Despite several larger scale attempts, genome-wide association studies (GWAS) have not led to the identification of significant results.

Genome-wide significant association between alcohol dependence and a variant in the ADH gene cluster.

Alcohol dependence (AD) is an important contributory factor to the global burden of disease. The etiology of AD involves both environmental and genetic factors, and the disorder has a heritability of around 50%. The aim of the present study was to identify susceptibility genes for AD by performing a genome-wide association study (GWAS).

Breakthroughs in the genetics of orofacial clefting.

Nonsyndromic orofacial clefts have a multifactorial etiology, involving both genetic and environmental factors. Although linkage and candidate gene studies have attempted to elucidate the underlying genetic architecture, only the interferon regulatory factor 6 (IRF6) gene has been identified as causative. The recent introduction of high-throughput genotyping technologies has enabled researchers to perform genome-wide association studies (GWAS).

A systematic eQTL study of cis-trans epistasis in 210 HapMap individuals.

We aimed at identifying transcripts whose expression is regulated by a SNP-SNP interaction. Out of 47,294 expression phenotypes we used 3107 transcripts that survived an extensive quality control and 86,613 linkage disequilibrium-pruned SNP markers that have been genotyped in 210 individuals. For each transcript we defined cis-SNPs, tested them for epistasis with all trans-SNPs, and corrected all observed cis-trans-regulated expression effects for multiple testing.

Common variation at 10p12.31 near MLLT10 influences meningioma risk.

To identify susceptibility loci for meningioma, we conducted a genome-wide association study of 859 affected individuals (cases) and 704 controls with validation in two independent sample sets totaling 774 cases and 1,764 controls. We identified a new susceptibility locus for meningioma at 10p12.31 (MLLT10, rs11012732, odds ratio = 1.

The effect of neurogranin on neural correlates of episodic memory encoding and retrieval.

Neurogranin (NRGN) is the main postsynaptic protein regulating the availability of calmodulin-Ca(2+) in neurons. NRGN is expressed exclusively in the brain, particularly in dendritic spines and has been implicated in spatial learning and hippocampal plasticity. Genetic variation in rs12807809 in the NRGN gene has recently been confirmed to be associated with schizophrenia in a meta-analysis of genome-wide association studies: the T-allele was found to be genome-wide significantly associated with schizophrenia.

Common variants at VRK2 and TCF4 conferring risk of schizophrenia.

Common sequence variants have recently joined rare structural polymorphisms as genetic factors with strong evidence for association with schizophrenia. Here we extend our previous genome-wide association study and meta-analysis (totalling 7 946 cases and 19 036 controls) by examining an expanded set of variants using an enlarged follow-up sample (up to 10 260 cases and 23 500 controls). In addition to previously reported alleles in the major histocompatibility complex region, near neurogranin (NRGN) and in an intron of transcription factor 4 (TCF4), we find two novel variants showing genome-wide significant association: rs2312147[C], upstream of vaccinia-related kinase 2 (VRK2) [odds ratio (OR) = 1.

Genetic determination of human facial morphology: links between cleft-lips and normal variation.

Recent genome-wide association studies have identified single nucleotide polymorphisms (SNPs) associated with non-syndromic cleft lip with or without cleft palate (NSCL/P), and other previous studies showed distinctly differing facial distance measurements when comparing unaffected relatives of NSCL/P patients with normal controls. Here, we test the hypothesis that genetic loci involved in NSCL/P also influence normal variation in facial morphology. We tested 11 SNPs from 10 genomic regions previously showing replicated evidence of association with NSCL/P for association with normal variation of nose width and bizygomatic distance in two cohorts from Germany (N=529) and the Netherlands (N=2497).

Phenotype severity in the bladder exstrophy-epispadias complex: analysis of genetic and nongenetic contributing factors in 441 families from North America and Europe.

Objective: To identify genetic and nongenetic risk factors that contribute to the severity of the bladder exstrophy-epispadias complex (BEEC).

Study Design: Patients with BEEC from North America (n = 167) and Europe (n = 274) were included. The following data were collected: associated anomalies, parental age at conception, mode of conception, periconceptional folic acid supplementation, maternal risk factors during pregnancy, and environmental risk factors.

Homozygosity mapping in 64 Syrian consanguineous families with non-specific intellectual disability reveals 11 novel loci and high heterogeneity.

Non-specific intellectual disability of autosomal recessive inheritance (NS-ARID) represents an important fraction of severe cognitive dysfunction disorders. To date, only 10 genes have been identified, and further 24 linked-ARID loci have been reported, as well as others with suggestive linkage. To discover novel genes causing NS-ARID, we undertook genome-wide homozygosity mapping in 64 consanguineous multiplex families of Syrian descent.

Adaptor protein complex 4 deficiency causes severe autosomal-recessive intellectual disability, progressive spastic paraplegia, shy character, and short stature.

Intellectual disability inherited in an autosomal-recessive fashion represents an important fraction of severe cognitive-dysfunction disorders. Yet, the extreme heterogeneity of these conditions markedly hampers gene identification. Here, we report on eight affected individuals who were from three consanguineous families and presented with severe intellectual disability, absent speech, shy character, stereotypic laughter, muscular hypotonia that progressed to spastic paraplegia, microcephaly, foot deformity, decreased muscle mass of the lower limbs, inability to walk, and growth retardation.

The neuronal transporter gene SLC6A15 confers risk to major depression.

Major depression (MD) is one of the most prevalent psychiatric disorders and a leading cause of loss in work productivity. A combination of genetic and environmental risk factors probably contributes to MD. We present data from a genome-wide association study revealing a neuron-specific neutral amino acid transporter (SLC6A15) as a susceptibility gene for MD.

Reduced cortical thickness is associated with the glutamatergic regulatory gene risk variant DAOA Arg30Lys in schizophrenia.

In light of current etiological concepts the glutamatergic system plays an essential role for the pathophysiology of the disorder, offering multiple options for new treatment strategies. The D-amino oxidase activator (DAOA) gene is closely connected to the glutamatergic system and its therapeutic and pathophysiological relevance for schizophrenia is therefore intensively debated. In a further step to shed light on the role of DAOA in schizophrenia, we aimed to investigate the association of the functional DAOA Arg30Lys (rs2391191) variant and cortical thickness in schizophrenia.

The genetics of panic disorder.

Panic disorder (PD) is one of the most common anxiety disorders, with a prevalence of 3.4-4.7%.

Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease.

We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ≤ 1 × 10(-5). We tested these variants for association in an independent sample (stage 2).

The complement control-related genes CSMD1 and CSMD2 associate to schizophrenia.

Background: Patients with schizophrenia often suffer from cognitive dysfunction, including impaired learning and memory. We recently demonstrated that long-term potentiation in rat hippocampus, a mechanistic model of learning and memory, is linked to gene expression changes in immunity-related processes involved in complement activity and antigen presentation. We therefore aimed to examine whether key regulators of these processes are genetic susceptibility factors in schizophrenia.

At-risk variant in TCF7L2 for type II diabetes increases risk of schizophrenia.

Background: Schizophrenia is associated with increased risk of type II diabetes and metabolic disorders. However, it is unclear whether this comorbidity reflects shared genetic risk factors, at-risk lifestyle, or side effects of antipsychotic medication.

Methods: Eleven known risk variants of type II diabetes were genotyped in patients with schizophrenia in a sample of 410 Danish patients, each matched with two healthy control subjects on sex, birth year, and month.

Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease.

We performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 individuals with CAD (cases) and 64,762 controls of European descent followed by genotyping of top association signals in 56,682 additional individuals. This analysis identified 13 loci newly associated with CAD at P < 5 × 10⁻⁸ and confirmed the association of 10 of 12 previously reported CAD loci. The 13 new loci showed risk allele frequencies ranging from 0.