Genetic associations between fibrinogen and cognitive performance in three Scottish cohorts.

There is increasing evidence to suggest that elevated plasma levels of fibrinogen are associated with late-life cognitive performance. This study tested the association of single nucleotide polymorphisms in the fibrinogen α (FGA) and ß (FGB) genes with cognitive performance. Data were analysed from three community-dwelling populations of older persons (>50 years) in central Scotland: the Aspirin for Asymptomatic Atherosclerosis (AAA) Trial (n = 2,091), the Edinburgh Type 2 Diabetes Study (ET2DS, n = 1,066), and the Lothian Birth Cohort 1936 (LBC1936, n = 1,091). Cognition was assessed using a battery of five, seven, and four psychometric tests, respectively. This information was used to derive a general cognitive factor. Weakly significant associations were found between the rs4220 (FGB), and rs2227412 (FGB) SNPs and a single test of cognitive performance in the AAA Trial (p < 0.05). These findings did not replicate in the LBC1936 or ET2DS cohorts, except for the rs2227412 SNP, which was significantly associated with the general cognitive factor in the ET2DS (p = 3.3 × 10(-4)). A summary term that combined results from all three studies suggested that the rs2227412 genotype associated with reduced cognitive ability also associated with higher plasma fibrinogen levels. These findings suggest a tentative role for fibrinogen as a determinant of late-life cognitive performance and justify further attempts at replication in older persons.

Variation in the uric acid transporter gene (SLC2A9) and memory performance.

Understanding human cognitive ageing is important to improve the health of an increasing elderly population. Serum uric acid levels have been linked to many ageing illnesses and are also linked to cognitive functioning, though the direction of the association is equivocal. SLC2A9, a urate transporter, influences uric acid levels. This study first tested four SLC2A9 SNPs, previously associated with uric acid levels, in approximately 1000 Scots: the Lothian Birth Cohort 1936 (LBC1936). These participants were tested on general cognitive ability at ages 11 and 70. At age 70, they took a battery of diverse cognitive tests. Two replication cohorts were investigated. First, the LBC1921, who were tested on general cognitive ability at age 11. At ages 79 (n = 520), 83 (n = 281) and age 87 (n = 177), they completed cognitive ability test batteries. Second, the Edinburgh Type 2 Diabetes Study (ET2DS) were tested for cognitive abilities aged between 60 and 75 years (n = 1066). All analyses were adjusted for age, gender, body mass index and either childhood cognitive ability test score (LBC) or vocabulary-a measure of prior cognitive ability in ET2DS. Significant associations were detected with SLC2A9 and a general memory factor in LBC1936 and other individual cognitive ability tests (lowest P = 0.0002). The association with logical memory replicated in LBC1921 at all ages (all P < 0.05). These associations were not replicated in ET2DS (all P > 0.1). If the positive associations withstand, then this study could suggest that higher uric acid levels may be associated with increased performance on memory-related tasks.

Common variants of large effect in F12, KNG1, and HRG are associated with activated partial thromboplastin time.

Activated partial thromboplastin time (aPTT) is associated with risk of thrombosis and coagulation disorders. We conducted a genome-wide association study for aPTT and identified significant associations with SNPs in three coagulation cascade genes, F12 (rs2731672, combined p = 2.16 x 10(-30)), KNG1 (rs710446, combined p = 9.52 x 10(-22)), and HRG (rs9898, combined p = 1.34 x 10(-11)). These three SNPs explain approximately 18% of phenotypic variance in aPTT in the Lothian Birth Cohorts.

Association of existing and new candidate genes for anxiety, depression and personality traits in older people.

Genetic variants that have previously been associated with personality traits and/or psychological distress, or inflammatory marker levels were investigated for their relationship to self-rated personality traits, anxiety, and depression in two elderly Scottish cohorts. Ten genes (29 SNPs) were investigated in the Lothian Birth Cohort 1936 (approximately 70 years, N = 1,091). Four of these genes and seven others (35 SNPs) were tested in the Lothian Birth Cohort 1921 who were measured on the same traits and states on two occasions (approximately 80 years, N = 550; 87 years, N = 229). For previously investigated candidate genes, some support (at a nominal significance level of 0.05/0.01) was found for association between NOS1 and personality traits (especially extraversion), PSEN1 and depression/neuroticism, and GRIK3 and depression. Of the inflammatory marker candidate genes, TF showed some association with psychological distress. No SNPs withstood the correction to significance level for multiple testing. Nevertheless, the results will be of importance to future meta-analyses of these candidate genes in relation to psychological distress and personality.

White matter integrity in the splenium of the corpus callosum is related to successful cognitive aging and partly mediates the protective effect of an ancestral polymorphism in ADRB2.

It has recently been reported that the evolutionarily ancestral alleles of two functional polymorphisms in the beta(2)-adrenergic receptor gene (ADRB2) were related to higher cognitive ability in the 70 year old participants of the Lothian Birth Cohort 1936 (LBC1936). One emerging important factor in cognitive aging is the integrity of white matter tracts in the brain. Here, we used diffusion tensor MRI-based tractography to assess the integrity of eight white matter tracts in a subsample of the LBC1936. Higher integrity of the splenium of the corpus callosum predicted better cognitive ability in old age, even after controlling for IQ at age 11. Also, the ancestral allele of one ADRB2 SNP was associated with both splenium integrity and better cognitive aging. While the effects of the SNP and splenium integrity on cognitive aging were largely independent, there was some evidence for a partial mediation effect of ADRB2 status via splenium integrity.

Genetic variants associated with altered plasma levels of C-reactive protein are not associated with late-life cognitive ability in four Scottish samples.

It is unknown whether the relationship between raised inflammatory biomarker levels and late-life cognitive ability is causal. We explored this issue by testing the association between genetic regulators of plasma C-reactive protein (CRP) and cognition. Data were analysed from four cohorts based in central Scotland (Total N = 4,782). Associations were tested between variants in the CRP gene and both plasma CRP levels and a battery of neuropsychological tests, including a vocabulary-based estimate of peak prior cognitive ability and a general (summary) cognitive factor score, or 'g'. CRP levels were associated with a number of variants in the CRP gene (SNPs), including rs1205, rs1130864, rs1800947, and rs1417938 (P range 4.2e-06 to 0.041). Higher CRP levels were also associated with vocabulary-adjusted cognitive ability, used here to estimate lifetime cognitive change (P range 1.7e-04 to 0.038). After correction for multiple testing and adjustment for age and sex, no statistically significant associations were found between the SNPs and cognition. CRP is unlikely to be a causal determinant of late-life cognitive ability.

Age-associated cognitive decline.

INTRODUCTION: Age-associated cognitive decline-or normal (non-pathological, normative, usual) cognitive ageing-is an important human experience which differs in extent between individuals. The determinants of the differences in age-related cognitive decline are not fully understood. Progress in the field is taking place across many areas of biomedical and psychosocial sciences. AREAS OF AGREEMENT AND CONTROVERSY: The phenotype of normal cognitive ageing is well described. Some mental capabilities are well maintained into old age. From early adulthood, there are declines in mental domains such as processing speed, reasoning, memory and executive functions, some of which is underpinned by a decline in a general cognitive factor. There are contributions to understanding individual differences in normal cognitive ageing from genetics, general health and medical disorders such as atherosclerotic disease, biological processes such as inflammation, neurobiological changes, diet and lifestyle. Many of these effect sizes are small; some are poorly replicated; and in some cases, there is the possibility of reverse causation, with prior cognitive ability causing the supposed 'cause' of cognitive ability in old age. EMERGING AREAS FOR DEVELOPING RESEARCH: Genome-wide scans are a likely source to establish genetic contributions. The role of vascular factors in cognitive ageing is increasingly studied and understood. The same applies to diet, biomarkers such as inflammation and lifestyle factors such as exercise. There are marked advances in brain imaging, affording better in vivo studies of brain correlates of cognitive changes. There is growing appreciation that factors affecting general bodily ageing also influence cognitive functions in old age.

Selected summaries from the XVI World Congress of Psychiatric Genetics, Osaka, Japan, 11-15 October 2008.

The XVI World Congress of Psychiatric Genetics, sponsored by the International Society of Psychiatric Genetics took place in Osaka, Japan, October 2008. Approximately 600 participants gathered to discuss the latest molecular genetic findings relevant to serious mental illnesses, including schizophrenia, bipolar disorder, major depression, alcohol and drug abuse, autism, and attention-deficit disorder. Recently, the field has advanced considerably and includes new genome-wide association studies with the largest numbers of individuals screened and density of markers to date, as well as newly uncovered genetic phenomena, such as copy number variation that may prove to be relevant for specific brain disorders. The following report represents some of the areas covered during this conference and some of the major new findings presented.

A case-control association study and family-based expression analysis of the bipolar disorder candidate gene PI4K2B.

Bipolar disorder, schizophrenia and recurrent major depression are complex psychiatric illnesses with a substantial, yet unknown genetic component. Linkage of bipolar disorder and recurrent major depression with markers on chromosome 4p15-p16 has been identified in a large Scottish family and three smaller families. Analysis of haplotypes in the four chromosome 4p-linked families, identified two regions, each shared by three of the four families, which are also supported by a case-control association study. The candidate gene phosphatidylinositol 4-kinase type-II beta (PI4K2B) lies within one of these regions. PI4K2B is a strong functional candidate as it is a member of the phosphatidylinositol pathway, which is targeted by lithium for therapeutic effect in bipolar disorder. Two approaches were undertaken to test the PI4K2B candidate gene as a susceptibility factor for psychiatric illness. First, a case-control association study, using tagging SNPs from the PI4K2B genomic region, in bipolar disorder (n=368), schizophrenia (n=386) and controls (n=458) showed association with a two-marker haplotype in schizophrenia but not bipolar disorder (rs10939038 and rs17408391, global P=0.005, permuted global P=0.039). Second, expression studies at the allele-specific mRNA and protein level using lymphoblastoid cell lines from members of the large Scottish family, which showed linkage to 4p15-p16 in bipolar disorder and recurrent major depression, showed no difference in expression differences between affected and non-affected family members. There is no evidence to suggest that PI4K2B is contributing to bipolar disorder in this family but a role for this gene in schizophrenia has not been excluded.

A Functional polymorphism under positive evolutionary selection in ADRB2 is associated with human intelligence with opposite effects in the young and the elderly.

Comparative genomics offers a novel approach to unravel the genetic basis of complex traits. We performed a two stage analysis where genes ascertained for enhanced protein evolution in primates are subsequently searched for the presence of non-synonymous coding SNPs in the current human population at amino acid sites that differ between humans and chimpanzee. Positively selected genes among primates are generally presumed to determine phenotypic differences between humans and chimpanzee, such as the enhanced cognitive ability of our species. Amino acid substitutions segregating in humans at positively selected amino acid sites are expected to affect phenotypic differences among humans. Therefore we conducted an association study in two family based cohorts and one population based cohort between cognitive ability and the most likely candidate gene among the five that harbored more than one such polymorphism. The derived, human-specific allele of the beta-2 adrenergic receptor Arg16Gly polymorphism was found to be the increaser allele for performance IQ in the young, family based cohort but the decreaser allele for two different measures of cognition in the large Scottish cohort of unrelated individuals. The polymorphism is known to affect signaling activity and modulation of beta-2 adrenergic signaling has been shown to adjust memory consolidation, a trait related to cognition. The opposite effect of the polymorphism on cognition in the two age classes observed in the different cohorts resembles the effect of ADRB2 on hypertension, which also has been reported to be age dependent. This result illustrates the relevance of comparative genomics to detect genes that are involved in human behavior.

Haplotype analysis and a novel allele-sharing method refines a chromosome 4p locus linked to bipolar affective disorder.

BACKGROUND: Bipolar affective disorder (BPAD) and schizophrenia (SCZ) are common conditions. Their causes are unknown, but they include a substantial genetic component. Previously, we described significant linkage of BPAD to a chromosome 4p locus within a large pedigree (F22). Others subsequently have found evidence for linkage of BPAD and SCZ to this region. METHODS: We constructed high-resolution haplotypes for four linked families, calculated logarithm of the odds (LOD) scores, and developed a novel method to assess the extent of allele sharing within genes between the families. RESULTS: We describe an increase in the F22 LOD score for this region. Definition and comparison of the linked haplotypes allowed us to prioritize two subregions of 3.8 and 4.4 Mb. Analysis of the extent of allele sharing within these subregions identified 200 kb that shows increased allele sharing between families. CONCLUSIONS: Linkage of BPAD to chromosome 4p has been strengthened. Haplotype analysis in the additional linked families refined the 20-Mb linkage region. Development of a novel allele-sharing method allowed us to bridge the gap between conventional linkage and association studies. Description of a 200-kb region of increased allele sharing prioritizes this region, which contains two functional candidate genes for BPAD, SLC2A9, and WDR1, for subsequent studies.