We conducted a genome-wide association study (GWAS) and a follow-up study of bipolar disorder (BD), a common neuropsychiatric disorder. In the GWAS, we investigated 499,494 autosomal and 12,484 X-chromosomal SNPs in 682 patients with BD and in 1300 controls. In the first follow-up step, we tested the most significant 48 SNPs in 1729 patients with BD and in 2313 controls. Eight SNPs showed nominally significant association with BD and were introduced to a meta-analysis of the GWAS and the first follow-up samples. Genetic variation in the neurocan gene (NCAN) showed genome-wide significant association with BD in 2411 patients and 3613 controls (rs1064395, p = 3.02 × 10(-8); odds ratio = 1.31). In a second follow-up step, we replicated this finding in independent samples of BD, totaling 6030 patients and 31,749 controls (p = 2.74 × 10(-4); odds ratio = 1.12). The combined analysis of all study samples yielded a p value of 2.14 × 10(-9) (odds ratio = 1.17). Our results provide evidence that rs1064395 is a common risk factor for BD. NCAN encodes neurocan, an extracellular matrix glycoprotein, which is thought to be involved in cell adhesion and migration. We found that expression in mice is localized within cortical and hippocampal areas. These areas are involved in cognition and emotion regulation and have previously been implicated in BD by neuropsychological, neuroimaging, and postmortem studies.

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Here we studied three phenotypic traits in Drosophila buzzatii that are strongly effected by temperature, and are expected to be closely associated with fitness in nature. The traits measured were thermal threshold of male sterility, time for males to gain fertility when reared at a sterility-inducing temperature and transferred to 251C on eclosion and survival after development. The last two traits were measured under four temperature regimes, constant 121C, 251C, 311C, and fluctuating 251C (18 h) and 381C (6 h). We looked for genetic variation in these traits and relations among them in four lines of D. buzzatii originating from Argentina and Tenerife. The thermal threshold of heat-induced male sterility was found to lie within the range of 30.0-31.01C. When measuring the time for males to gain fertility, males reared at a nonstressful temperature (251C) were fertile 58-67 h after emergence with only minor differences among lines. When reared constant 311C, males were fertile 174-225 h after hatching. The Argentinean lines were significantly faster in recovering from sterility than were the lines from Tenerife. When reared in a fluctuating temperature regime, differences among lines increased, dividing the lines into three significantly different groups, with a sterility period of 135-215 h. When reared at 121C from the pupal stage, males were fertile after 106-130 h with significant difference in the variance but not in the mean duration of sterility. Significant differences in viability were found among development temperatures, but not among lines, and viability and the duration of sterility seem to be genetically independent.