We report the first genome-wide association study in 1000 bipolar I patients and 1000 controls, with a replication of the top hits in another 409 cases and 1000 controls in the Han Chinese population. Four regions with most strongly associated single-nucleotide polymorphisms (SNPs) were detected, of which three were not found in previous GWA studies in the Caucasian populations. Among them, SNPs close to specificity protein 8 (SP8) and ST8 a-Nacetyl-neuraminide a-2,8-sialyltransferase (ST8SIA2) are associated with Bipolar I, with Pvalues of 4.87 Â 10 À7 (rs2709736) and 6.05 Â 10 À6 (rs8040009), respectively. We have also identified SNPs in potassium channel tetramerization domain containing 12 gene (KCTD12) (rs2073831, P = 9.74 Â 10 À6 ) and in CACNB2 (Calcium channel, voltage-dependent, b-2 subunit) gene (rs11013860, P = 5.15 Â 10 À5 ), One SNP nearby the rs1938526 SNP of ANK3 gene and another SNP nearby the SNP rs11720452 in chromosome 3 reported in previous GWA studies also showed suggestive association in this study (P = 6.55 Â 10 À5 and P = 1.48 Â 10 À5 , respectively). This may suggest that there are common and population-specific susceptibility genes for bipolar I disorder.

Nitric oxide (NO) plays a major role in the pulmonary host-defence mechanism in response to infections and is implicated in bacteriostatic as well as bactericidal processes [1,2]. NO is generated through the L-arginine pathway and is converted to the related reactive nitrogen intermediates (RNI) . In inflammatory responses, NO is produced by the inducible form of NO synthase (iNOS), which is mostly from inflammatory cells, such as macrophages [3][4][5]. NO production and iNOS expression by alveolar macrophages (AM) is upregulated in response to heat-killed Mycobacterium tuberculosis instilled into the lungs of rats [6] and plays a role in limiting the growth of Mycobacterium avium complex [7,8]. Murine macrophages activated by interferon (IFN)-γ and tumour necrosis factor (TNF)-α are capable of killing M. tuberculosis in vitro via the generation of RNI by iNOS [9]. In addition, pretreatment with NO synthase (NOS) inhibitors profoundly increases bacterial burden, pathological tissue damage and mortality in mice infected with M. tuberculosis [10], thus indicating that NO plays an important role in resistance to M. tuberculosis infection in the mouse. A recent report has shown that iNOS messenger ribonucleic acid (mRNA) is upregulated on AM in patients with active pulmonary tuberculosis (TB) [11], however, it is not known whether the iNOS enzyme activity is also enhanced and leads to increased generation of RNI by AM against M. tuberculosis.NO can be detected in the expired air of animals and humans [12]. Recent reports have shown that the level of exhaled NO is elevated in patients with bronchial asthma and bronchiectasis [13,14], and have suggested that this is due to iNOS upregulation induced by cytokines such as IFN-γ, TNF-α and interleukin (IL)-1β [15] released in chronic airway inflammation. Thus, the measure of exhaled NO concentration may gauge the extent of NOmediated inflammatory responses in the airways. In this study, we measured exhaled NO levels in patients with active pulmonary TB and determined the cellular source of NO by examining the expression of iNOS and the release of RNI from AM. Material and methods Study populationNineteen patients with active pulmonary TB (13 males and 6 females, aged 59.1±4.5 yrs) were studied prior to anti-TB treatment. None of these patients were current smokers. For all patients, at least one recent sputum specimen We conclude that the increase in exhaled nitric oxide observed in patients with active pulmonary tuberculosis is due to an upregulation of inhaled NO synthase expression in alveolar macrophages which have an enhanced capacity for nitric oxide production. Eur Respir J 1998; 11: 809-815.