Gang Chen

Familial clustering of schizophrenia (SCZ), bipolar disorder (BPD), and major depressive disorder (MDD) was investigated systematically (Aukes et al., Genetics in Medicine, 2012, 14, 338–341) and any two or even three of these disorders could coexist in some families. Furthermore, evidence from symptomatology and psychopharmacology also imply the existence of intrinsic connections between these three major psychiatric disorders. A total of 71,445 SNPs on chromosome 1 were genotyped on 119 SCZ, 253 BPD (type‐I), 177 MDD cases and 1000 controls and further validated in 986 SCZ patients in the population of Shandong province of China. Outstanding psychosis genes are systematically revealed( ATP1A4, ELTD1, FAM5C, HHAT, KIF26B, LMX1A, NEGR1, NFIA, NR5A2, NTNG1, PAPPA2, PDE4B, PEX14, RYR2, SYT6, TGFBR3, TTLL7, and USH2A). Unexpectedly, flanking genes for up to 97.09% of the associated SNPs were also replicated in an enlarged cohort of 986 SCZ patients. From the perspective of etiological rather than clinical psychiatry, bipolar, and major depressive disorder could be subtypes of schizophrenia. Meanwhile, the varied clinical feature and prognosis might be the result of interaction of genetics and epigenetics, for example, irreversible or reversible shut down, and over or insufficient expression of certain genes, which may gives other aspects of these severe mental disorders.

Convergent evidence from genetics, symptomatology, and psychopharmacology imply that there are intrinsic connections between schizophrenia (SCZ), bipolar disorder (BPD), and major depressive disorder (MDD). Familial clustering of SCZ, BPD, and MDD was systematically investigated [Aukes et al. (2012); Genetics in Medicine 14(3): 338–341], and any two or even three of these disorders could co‐exist in some families. A total of 56,134 SNPs on chromosome 4 were genotyped by Affymetrix Genome‐Wide Human SNP array 6.0 on 119 SCZ, 253 BPD (Type‐I), 177 MDD patients, and 1,000 controls in a relative homogenous population in China. Susceptibility genes on chromosome 4 for the three major psychiatric disorders were systematically identified including outstanding genes (CXCL13, FSTL5, GLRB, KCNIP4, LPHN3, MAPK10, NPFFR2, NSUN7, PCDH10, PCDH7, PPA2, PPARGC1A, SCD5, SCFD2, and UNC5C). Unexpectedly, flanking genes for up to 93.67% of the associated SNPs were also confirmed in an enlarged cohort of 986 SCZ patients. Taken all relevant evidence together, our chromosome 4 results implicate that both of bipolar and major depressive disorders might be subtypes of SCZ rather than independent disease entity. Furthermore, similar evidence was also observed on chromosome 3, 5, 6, 7, and 8 [2018; The Journal of Comparative Neurology 526(1):59–79; Chen et al. (2017); American Journal of Translational Research 9(5):2473–2491; Chen et al. (2016); Current Molecular Medicine, 16(9):840–854; Chen et al. (2015); Behavioural Brain Research, 293:241–51; Chen et al. (2016); Molecular Neurobiology, 54(8):5868–5882].

Familial clustering of schizophrenia (SCZ), bipolar disorder (BPD), and major depressive disorder (MDD) was systematically reported (Aukes et al, Genet Med 2012, 14, 338‐341) and convergent evidence from genetics, symptomatology, and psychopharmacology imply that there are intrinsic connections between these three major psychiatric disorders, for example, any two or even three of these disorders could co‐exist in some families. A total of 60, 838 single‐nucleotide polymorphisms (SNPs) on chromosome 3 were genotyped by Affymetrix Genome‐Wide Human SNP array 6.0 on 119 SCZ, 253 BPD (type‐I), 177 MDD patients and 1,000 controls. Thepopulation ofShandong province was formed in 14 century and believed that it belongs to homogenous population. Associated SNPs were systematically revealed and outstanding susceptibility genes (CADPS, GRM7,KALRN, LSAMP, NLGN1, PRICKLE2, ROBO2) were identified. Unexpectedly, flanking genes for the associated SNPs distinctive for BPD and/or MDD were replicated in an enlarged cohort of 986 SCZ patients. The evidence from this chromosome 3 analysis supports the notion that both of bipolar and MDD might be subtypes of schizophrenia rather than independent disease entity. Also, a similar finding was detected on chromosome 5, 6, 7, and 8 (Chen et al. Am J Transl Res 2017;9 (5):2473–2491; Curr Mol Med 2016;16(9):840–854; Behav Brain Res 2015;293:241–251; Mol Neurobiol 2016. doi: 10.1007/s12035‐016‐0102‐1). Furthermore,PRICKLE2play an important role in the pathogenesis of three major psychoses in this population.

Familial clustering of schizophrenia (SCZ), bipolar disorder (BPD), and major depressive disorder (MDD) was systematically reported (Aukes, M. F. Genet Med 2012, 14, 338-341) and any two or even three of these disorders could co-exist in some families. In addition, evidence from symptomatology and psychopharmacology also imply that there are intrinsic connections between these three major disorders. A total of 56,569 single nucleotide polymorphism (SNPs) on chromosome 5 were genotyped by Affymetrix Genome-Wide Human SNP array 6.0 on 119 SCZ, 253 BPD (type-I), 177 MDD patients and 1000 controls. Associated SNPs and flanking genes was screen out systematically, and cadherin pathway genes (CDH6, CDH9, CDH10, CDH12, and CDH18) belong to outstanding genes. Unexpectedly, nearly all flanking genes of the associated SNPs distinctive for BPD and MDD were replicated in an enlarged cohort of 986 SCZ patients (P ≤ 9.9E-8). Considering multiple bits of evidence, our chromosome 5 analyses implicated that bipolar and major depressive disorder might be subtypes of schizophrenia rather than two independent disease entities. Also, cadherin pathway genes play important roles in the pathogenesis of the three major mental disorders.

Convergent evidence from genetics, symptomatology, and psychopharmacology implies that there are intrinsic connections between schizophrenia (SCZ), bipolar disorder (BPD), and major depressive disorder (MDD); for example, any two or even three of these disorders could co-exist in some families. A total of 48,753 single nucleotide polymorphisms (SNPs) on chromosome 8 were genotyped by Affymetrix Genome-Wide Human SNP array 6.0 on 119 SCZ, 253 BPD (type I), 177 MDD patients, and 1000 controls. Associated SNP loci were comprehensively revealed, and outstanding susceptibility genes were identified including CSMD1, NRG1, PXDNL, SGCZ, and TMEM66. Unexpectedly, flanking genes for up to 95.9 % of the associated SNPs were replicated (P ≤ 9.9E−8) in the enlarged cohort of 986 SCZ patients. Considering convergent evidence, our results implicate that bipolar disorder and major depressive disorder might be subtypes of schizophrenia.

Maturity-onset diabetes of the young (MODY) is a heterogeneous entity of monogenic disorders characterized by autosomal dominant inheritance. Eleven genes were related, including HNF4α, GCK, HNF1α, IPF1, and HNF-1β, and various mutations are being reported. To help the overall understanding of MODY-related pathologic mutations, we studied a large MODY family found in 2012, in Shandong, China, which contained 9 patients over 3 generations. DNA was extracted from the periphery blood samples of (i) 9 affected members, (ii) 17 unaffected members, and (iii) 1000 healthy controls. Three pooled samples were obtained by mixing equal quantity of DNA of each individual within the each group. Totally 400 microsatellite markers across the whole genome were genotyped by capillary electrophoresis. The known MODY-related gene near the identified marker was sequenced to look for putative risk variants. Allelic frequency of marker D17S798 on chromosome 17q11.2 were significantly different (P<0.001) between the affected vs. unaffected members and the affected vs. healthy controls, but not between the unaffected members vs. healthy controls. MODY5-related gene, hepatocyte nuclear factor-1β (HNF-1β) on 17q12 near D17S798 became the candidate gene. A single nucleotide variant (SNV) of C77T in the non-coding area of exon 1 of HNF-1β was found to be related to MODY5. This novel SNV of HNF-1β contributes to the diabetes development in the family through regulating gene expression most likely. The findings help presymptomatic diagnosis, and imply that mutations in the non-coding areas, as well as in the exons, play roles in the etiology of MODY.