Helen M. Knight

A genome-wide association study implicates the APOE locus in nonpathological cognitive ageing

Cognitive decline is a feared aspect of growing old. It is a major contributor to lower quality of life and loss of independence in old age. We investigated the genetic contribution to individual differences in nonpathological cognitive ageing in five cohorts of older adults. We undertook a genome-wide association analysis using 549u2009692 single-nucleotide polymorphisms (SNPs) in 3511 unrelated adults in the Cognitive Ageing Genetics in England and Scotland (CAGES) project. These individuals have detailed longitudinal cognitive data from which phenotypes measuring each individual’s cognitive changes were constructed. One SNP—rs2075650, located in TOMM40 (translocase of the outer mitochondrial membrane 40 homolog)—had a genome-wide significant association with cognitive ageing (P=2.5 × 10−8). This result was replicated in a meta-analysis of three independent Swedish cohorts (P=2.41 × 10−6). An Apolipoprotein E (APOE) haplotype (adjacent to TOMM40), previously associated with cognitive ageing, had a significant effect on cognitive ageing in the CAGES sample (P=2.18 × 10−8; females, P=1.66 × 10−11; males, P=0.01). Fine SNP mapping of the TOMM40/APOE region identified both APOE (rs429358; P=3.66 × 10−11) and TOMM40 (rs11556505; P=2.45 × 10−8) as loci that were associated with cognitive ageing. Imputation and conditional analyses in the discovery and replication cohorts strongly suggest that this effect is due to APOE (rs429358). Functional genomic analysis indicated that SNPs in the TOMM40/APOE region have a functional, regulatory non-protein-coding effect. The APOE region is significantly associated with nonpathological cognitive ageing. The identity and mechanism of one or multiple causal variants remain unclear.

A Cytogenetic Abnormality and Rare Coding Variants Identify ABCA13 as a Candidate Gene in Schizophrenia, Bipolar Disorder, and Depression

Schizophrenia and bipolar disorder are leading causes of morbidity across all populations, with heritability estimates of approximately 80% indicating a substantial genetic component. Population genetics and genome-wide association studies suggest an overlap of genetic risk factors between these illnesses but it is unclear how this genetic component is divided between common gene polymorphisms, rare genomic copy number variants, and rare gene sequence mutations. We report evidence that the lipid transporter gene ABCA13 is a susceptibility factor for both schizophrenia and bipolar disorder. After the initial discovery of its disruption by a chromosome abnormality in a person with schizophrenia, we resequenced ABCA13 exons in 100 cases with schizophrenia and 100 controls. Multiple rare coding variants were identified including one nonsense and nine missense mutations and compound heterozygosity/homozygosity in six cases. Variants were genotyped in additional schizophrenia, bipolar, depression (n > 1600), and control (n > 950) cohorts and the frequency of all rare variants combined was greater than controls in schizophrenia (OR = 1.93, p = 0.0057) and bipolar disorder (OR = 2.71, p = 0.00007). The population attributable risk of these mutations was 2.2% for schizophrenia and 4.0% for bipolar disorder. In a study of 21 families of mutation carriers, we genotyped affected and unaffected relatives and found significant linkage (LOD = 4.3) of rare variants with a phenotype including schizophrenia, bipolar disorder, and major depression. These data identify a candidate gene, highlight the genetic overlap between schizophrenia, bipolar disorder, and depression, and suggest that rare coding variants may contribute significantly to risk of these disorders.

A common variant in the 3′UTR of the GRIK4 glutamate receptor gene affects transcript abundance and protects against bipolar disorder

Underactivity of the glutamatergic system is an attractive model for the pathophysiology of several major mental illnesses. We previously described a chromosome abnormality disrupting the kainate class ionotropic glutamate receptor gene, GRIK4/KA1, in an individual with schizophrenia and learning disability (mental retardation). We also demonstrated in a case-control study that two physically separated haplotypes within this gene were significantly associated with increased risk of schizophrenia and decreased risk of bipolar disorder, respectively. The latter protective haplotype was located at the 3′ end of the gene. We now report the identification from carriers of the protective haplotype of a deletion variant within the 3′ untranslated region of the gene. The deletion allele also was found to be negatively associated with bipolar disorder in both initial (P = 0.00000019) and replication (P = 0.0107) case-control studies. Expression studies indicated that deletion-carrying mRNA transcripts were relatively more abundant. We postulate that this may be a direct consequence of the differences in the RNA secondary structures predicted for the insertion and deletion alleles. These data suggest a mechanism whereby the genetic protective effect is mediated through increased kainate receptor expression.

Homozygosity mapping in a family presenting with schizophrenia, epilepsy and hearing impairment

Homozygosity mapping within consanguineous families is a powerful method of localising genes for autosomal recessive disease. We investigated a family from Punjab, Pakistan, a region where consanguineous marriages are frequent. The parents have no detectable clinical disorders. However, five out of six children present with schizophrenia, epilepsy or hearing impairment either alone or in combination. This unusual phenotype in several offspring of first cousins is strongly suggestive of a rare, Mendelian recessive disorder. Two genome-wide scans initially using low-density microsatellites, and subsequently high-density SNP markers were used to map homozygous-by-descent regions in affected individuals. Candidate genes within these loci were subsequently screened for mutations. Homozygosity analysis and inbreeding coefficients were investigated to give an estimate of consanguinity. Two putative disease loci were mapped to 22q12.3–q13.3 and 2p24.3. The candidate locus on chromosome 2p24 overlaps with a deafness locus, DFNB47, linked to autosomal recessive hearing impairment, while positive findings reported for affective psychosis and schizophrenia cluster in a region of 4–5u2009cM on 22q13.1 within our second candidate locus. Sequence analysis of three candidate genes (KCNF1 (2p); ATF4, CACNG2 (22q)) did not reveal any exonic mutations. Inbreeding coefficients calculated for each family member support a very high degree of ancestral and recent inbreeding. The screening of other candidate genes located within these newly identified disease intervals on Chr2p24.3 and 22q12.3-q13.3 may lead to the discovery of causative variants, and consequent disrupted molecular pathways associated with this rare phenotype.

GRIK4/KA1 protein expression in human brain and correlation with bipolar disorder risk variant status

The kainate class of ionotropic glutamate receptors is involved in the regulation of neuronal transmission and synaptic plasticity. Previously we reported that a deletion variant within the gene GRIK4, which encodes the KA1 kainate receptor subunit, was associated with a reduced risk of bipolar disorder and increased GRIK4 mRNA abundance. Using a high resolution immunohistochemistry technique, we characterized KA1 protein localization in human brain and performed a genotype–protein expression correlation study. KA1 was expressed in specific populations of neuronal cells in the cerebellum and all layers of the frontal and parahippocampal cortices. In the hippocampus, strong KA1 expression was observed in the stratum pyramidale and stratum lucidum of CA3 and CA2, in cell processes in CA1, in the neuropil of the CA4 region, in polymorphic cells including mossy fiber neurons in the hilus, and dentate gyrus (DG) granule cells. Mean counts of KA1 positive DG granule cells, hippocampal CA3 pyramidal cells, and layer 1 of the frontal cortex were significantly increased in subjects with the deletion allele (Pu2009=u20090.0005, 0.018, and 0.0058, respectively) compared to subjects homozygous for the insertion. Neuronal expression levels in all regions quantified were higher in the deletion group. These results support our hypothesis that the deletion allele affords protection against bipolar disorder through increased KA1 protein abundance in neuronal cells. Biological mechanisms which may contribute to this protective effect include KA1 involvement in adult hippocampal neurogenesis, HPA axis activation, or plasticity processes affecting neuronal circuitry.

Cognitive endophenotypes in a family with bipolar disorder with a risk locus on chromosome 4.

OBJECTIVESnu2002 We studied cognitive function in high-risk relatives belonging to a single extended family showing linkage of bipolar disorder to a locus on chromosome 4. High-risk relatives were defined as those that carried the risk haplotype of polymorphic markers, identified in a previous linkage study. This family provided a rare opportunity to characterize a neuropsychological endophenotype in a homogeneous sample of relatives with a common genetic risk factor.nnnMETHODSnu2002 Fifteen family members carrying the risk haplotype (eight diagnosed with bipolar disorder or depression and seven with no psychiatric diagnosis), unrelated patients with bipolar disorder (nu2003=u200336) and major depressive disorder (nu2003=u200340), and healthy control subjects (nu2003=u200333) were administered the California Verbal Learning Test, Verbal Fluency Test, Hayling Sentence Completion Test, and Brixton Spatial Anticipation Test to assess verbal memory, verbal fluency, and executive function.nnnRESULTSnu2002 Compared with healthy controls, family members carrying the risk haplotype were impaired in indices of memory and executive function. There were no significant differences between unaffected and affected haplotype-carrying family members in any cognitive measure. Pronounced deficits in the encoding stage of verbal memory and category verbal fluency were evident in individuals with the risk haplotype.nnnCONCLUSIONSnu2002 Verbal learning and semantic verbal fluency impairments may represent a cognitive endophenotype for both bipolar disorder and major depression in relatives of bipolar disorder patients, as impairment was also present in high-risk relatives who had not developed any affective disorder symptoms. These findings suggest that impairment in semantic organization may be linked to the genetic aetiology of bipolar disorder.

A kainate receptor GluK4 deletion, protective against bipolar disorder, is associated with enhanced cognitive performance across diagnoses in the TwinsUK cohort

Abstract Objectives: Cognitive deficits are a common feature of neuropsychiatric disorders. We investigated the relationship between cognitive performance and a deletion allele within GluK4 protective against risk for bipolar disorder, in 1,642 individuals from the TwinsUK study. Methods: Cognitive performance was assessed using the National Adult Reading Test, four CANTAB tests (Spatial Working Memory, Paired Associates Learning, Pattern Recognition Memory and Reaction Time), and two Principal-Component Analysis-derived factors. Performance in individuals homozygous for the insertion allele was compared to deletion carriers and analysis was adjusted for age of diagnosis, medication and clinical diagnosis. Results: Individuals with the GluK4 protective deletion allele performed significantly better in Spatial Working Memory compared to insertion homozygotes when adjusted for a clinical diagnosis. GluK4 deletion carriers who had a mental health problem (predominately depression) showed better performance in visuo-spatial ability and mental processing speed compared to individuals with mental health problems homozygous for the insertion. Conclusions: These findings of genotype-dependent cognitive enhancement across clinical groups support the potential clinical use of the GluK4 deletion allele in personalised medicine strategies and provide new insight into the relationship between genetic variation and mood disorders.

Vitamin intake is associated with improved visuospatial and verbal semantic memory in middle-aged individuals

Objectives: Factors maintaining cognitive health are still largely unknown. In particular, the cognitive benefits associated with vitamin intake and vitamin supplementation are disputed. We investigated self-reported vitamin intake and serum vitamin levels with performance in cognitive factors sensitive to dementia progression in two large middle-aged general population cohorts. Methods: Survey data were used to assess regular vitamin intake in 4400 NCDS 1958 and 1177 TwinsUK cohort members, and serum homocysteine and B vitamin levels were measured in 675 individuals from the TwinsUK study. Principal component analysis was applied to cognitive test performance from both cohorts resulting in two dementia-sensitive cognitive factors reflecting visuospatial associative memory and verbal semantic memory. Results: In both cohorts, individuals who reported regular intake of vitamins, particularly B vitamins, showed significantly better performance in visuospatial associative memory and verbal semantic memory (Pu2009<u20090.001). A significant association was also found between homocysteine levels, vitamin serum concentration and visuospatial associative memory performance which indicated that individuals with high B vitamin and homocysteine levels showed better visuospatial associative memory performance than individuals with low vitamin B levels (Pu2009<u20090.05). Discussion: The findings demonstrate that early dementia-sensitive cognitive changes can be identified in middle-aged asymptomatic individuals and that regular vitamin intake is associated with improved cognitive performance. These findings reinforce the potential cognitive benefits of regular vitamin intake, which should be considered as an economically viable therapeutic strategy for maintaining cognitive health.

Genetic Predispositions to Stressful Conditions

The nature and number of stressful events a person experiences are the result of interactions between a persons genetic makeup and their environment. Genes influence a persons response to stress and how much stress a person is exposed to. Several biological mechanisms have been proposed to mediate gene–environment interactions.