M G McInnis

Publications of M G McInnis

• Enrichment of cis-regulatory gene expression SNPs and methylation quantitative trait loci among bipolar disorder susceptibility variants.

  Authors: E R Gamazon, J A Badner, L Cheng, C Zhang, D Zhang, N J Cox, E S Gershon, J R Kelsoe, T A Greenwood, C M Nievergelt [......] J B Potash, P P Zandi, P B Mahon, M G McInnis, S Zöllner, P Zhang, D W Craig, S Szelinger, T B Barrett, C Liu

  Molecular psychiatry. 01/2012;

  We conducted a systematic study of top susceptibility variants from a genome-wide association (GWA) study of bipolar disorder to gain insight into the functional consequences of genetic variationWe conducted a systematic study of top susceptibility variants from a genome-wide association (GWA) study of bipolar disorder to gain insight into the functional consequences of genetic variation influencing disease risk. We report here the results of experiments to explore the effects of these susceptibility variants on DNA methylation and mRNA expression in human cerebellum samples. Among the top susceptibility variants, we identified an enrichment of cis regulatory loci on mRNA expression (eQTLs), and a significant excess of quantitative trait loci for DNA CpG methylation, hereafter referred to as methylation quantitative trait loci (mQTLs). Bipolar disorder susceptibility variants that cis regulate both cerebellar expression and methylation of the same gene are a very small proportion of bipolar disorder susceptibility variants. This finding suggests that mQTLs and eQTLs provide orthogonal ways of functionally annotating genetic variation within the context of studies of pathophysiology in brain. No lymphocyte mQTL enrichment was found, suggesting that mQTL enrichment was specific to the cerebellum, in contrast to eQTLs. Separately, we found that using mQTL information to restrict the number of single-nucleotide polymorphisms studied enhances our ability to detect a significant association. With this restriction a priori informed by the observed functional enrichment, we identified a significant association (rs12618769, P(bonferroni)<0.05) from two other GWA studies (TGen+GAIN; 2191 cases and 1434 controls) of bipolar disorder, which we replicated in an independent GWA study (WTCCC). Collectively, our findings highlight the importance of integrating functional annotation of genetic variants for gene expression and DNA methylation to advance the biological understanding of bipolar disorder.Molecular Psychiatry advance online publication, 3 January 2012; doi:10.1038/mp.2011.174.

• Genome-wide association study of bipolar disorder in European American and African American individuals.

  Authors: E N Smith, C S Bloss, J A Badner, T Barrett, P L Belmonte, W Berrettini, W Byerley, W Coryell, D Craig, H J Edenberg [......] J B Potash, J Rice, T G Schulze, W Scheftner, C Panganiban, N Zaitlen, P P Zandi, S Zöllner, N J Schork, J R Kelsoe

  Molecular psychiatry. 07/2009;

  To identify bipolar disorder (BD) genetic susceptibility factors, we conducted two genome-wide association (GWA) studies: one involving a sample of individuals of European ancestry (EA; n=1001 cases;To identify bipolar disorder (BD) genetic susceptibility factors, we conducted two genome-wide association (GWA) studies: one involving a sample of individuals of European ancestry (EA; n=1001 cases; n=1033 controls), and one involving a sample of individuals of African ancestry (AA; n=345 cases; n=670 controls). For the EA sample, single-nucleotide polymorphisms (SNPs) with the strongest statistical evidence for association included rs5907577 in an intergenic region at Xq27.1 (P=1.6 x 10(-6)) and rs10193871 in NAP5 at 2q21.2 (P=9.8 x 10(-6)). For the AA sample, SNPs with the strongest statistical evidence for association included rs2111504 in DPY19L3 at 19q13.11 (P=1.5 x 10(-6)) and rs2769605 in NTRK2 at 9q21.33 (P=4.5 x 10(-5)). We also investigated whether we could provide support for three regions previously associated with BD, and we showed that the ANK3 region replicates in our sample, along with some support for C15Orf53; other evidence implicates BD candidate genes such as SLITRK2. We also tested the hypothesis that BD susceptibility variants exhibit genetic background-dependent effects. SNPs with the strongest statistical evidence for genetic background effects included rs11208285 in ROR1 at 1p31.3 (P=1.4 x 10(-6)), rs4657247 in RGS5 at 1q23.3 (P=4.1 x 10(-6)), and rs7078071 in BTBD16 at 10q26.13 (P=4.5 x 10(-6)). This study is the first to conduct GWA of BD in individuals of AA and suggests that genetic variations that contribute to BD may vary as a function of ancestry.Molecular Psychiatry advance online publication, 2 June 2009; doi:10.1038/mp.2009.43.

• Singleton deletions throughout the genome increase risk of bipolar disorder.

  Authors: D Zhang, L Cheng, Y Qian, N Alliey-Rodriguez, J R Kelsoe, T Greenwood, C Nievergelt, T B Barrett, R McKinney, N Schork [......] P L Belmonte, P P Zandi, M G McInnis, S Zöllner, D Craig, S Szelinger, D Koller, S L Christian, C Liu, E S Gershon

  Molecular psychiatry. 01/2009;

  An overall burden of rare structural genomic variants has not been reported in bipolar disorder (BD), although there have been reports of cases with microduplication and microdeletion. Here, weAn overall burden of rare structural genomic variants has not been reported in bipolar disorder (BD), although there have been reports of cases with microduplication and microdeletion. Here, we present a genome-wide copy number variant (CNV) survey of 1001 cases and 1034 controls using the Affymetrix single nucleotide polymorphism (SNP) 6.0 SNP and CNV platform. Singleton deletions (deletions that appear only once in the dataset) more than 100 kb in length are present in 16.2% of BD cases in contrast to 12.3% of controls (permutation P=0.007). This effect was more pronounced for age at onset of mania </=18 years old. Our results strongly suggest that BD can result from the effects of multiple rare structural variants.Molecular Psychiatry advance online publication, 30 December 2008; doi:10.1038/mp.2008.144.

• Genome-wide linkage scan of 98 bipolar pedigrees and analysis of clinical covariates.

  Authors: P P Zandi, J A Badner, J Steele, V L Willour, K Miao, D F MacKinnon, F M Mondimore, B Schweizer, M G McInnis, J R DePaulo, E Gershon, F J McMahon, J B Potash

  Molecular psychiatry. 08/2007; 12(7):630-9.

  Despite compelling evidence that genetic factors contribute to bipolar disorder (BP), attempts to identify susceptibility genes have met with limited success. This may be due to the geneticDespite compelling evidence that genetic factors contribute to bipolar disorder (BP), attempts to identify susceptibility genes have met with limited success. This may be due to the genetic heterogeneity of the disorder. We sought to identify susceptibility loci for BP in a genome-wide linkage scan with and without clinical covariates that might reflect the underlying heterogeneity of the disorder. We genotyped 428 subjects in 98 BP families at the Center for Inherited Disease Research with 402 microsatellite markers. We first carried out a non-parametric linkage analysis with MERLIN, and then reanalyzed the data with LODPAL to incorporate clinical covariates for age at onset (AAO), psychosis and comorbid anxiety. We sought to further examine the top findings in the covariate analysis in an independent sample of 64 previously collected BP families. In the non-parametric linkage analysis, three loci were nominally significant under a narrow diagnostic model and seven other loci were nominally significant under a broader model. The top findings were on chromosomes 2q24 and 3q28. The covariate analyses yielded additional evidence for linkage on 3q28 with AAO in the primary and independent samples. Although none of the linked loci were genome-wide significant, their congruence with prior results and, for the covariate analyses, their identification in two separate samples increases the likelihood that they are true positives and deserve further investigation. These findings further demonstrate the value of considering clinical features that may reflect the underlying heterogeneity of disease in order to facilitate gene mapping.

• Linkage of bipolar affective disorder on chromosome 8q24: follow-up and parametric analysis.

  Authors: D Avramopoulos, V L Willour, P P Zandi, Y Huo, D F MacKinnon, J B Potash, J R DePaulo, M G McInnis

  Molecular psychiatry. 03/2004; 9(2):191-6.

  Our group first reported a linkage finding for bipolar (BP) disorder on chromosome 8q24 in a study of 50 multiplex pedigrees, with an HLOD score reaching 2.39. Recently, Cichon et al reported an LODOur group first reported a linkage finding for bipolar (BP) disorder on chromosome 8q24 in a study of 50 multiplex pedigrees, with an HLOD score reaching 2.39. Recently, Cichon et al reported an LOD score of 3.62 in the same region using two-point parametric analysis. Subsequently, we published the results of a genome scan for linkage to BP disorder using a sample extended to 65 pedigrees in which chromosome 8q24 provided the best finding, an NPL score of 3.13, approaching the accepted score for suggestive linkage. We have now fine mapped this region of chromosome 8 in our 65 pedigrees by the addition of 19 microsatellite markers reaching a marker density of 0.8 cM and an information content of 0.84. After the addition of the new data, the original NPL score slightly increased to 3.25. Two-point parametric analysis using the model employed by Cichon et al obtained an LOD score of 3.32 for marker D8S256 at theta=0.14 exceeding the proposed threshold for genomewide significance. After adjusting the parameters in accordance with the 'common disease-common variant' hypothesis, multipoint parametric analysis resulted in an HLOD of 2.49 (alpha=0.78) between D8S529 and D8S256, and defined a 1-LOD interval corresponding to a 2.3 Mb region. No allelic association with the disease was observed for our set of microsatellite markers. Biologically, plausible candidate genes in this region include thyroglobulin, KCNQ3 coding for a voltage-gated potassium channel and the gene for brain adenyl-cyclase (ADCY8).

• Findings in an independent sample support an association between bipolar affective disorder and the G72/G30 locus on chromosome 13q33.

  Authors: Y S Chen, N Akula, S D Detera-Wadleigh, T G Schulze, J Thomas, J B Potash, J R DePaulo, M G McInnis, N J Cox, F J McMahon

  Molecular psychiatry. 02/2004; 9(1):87-92; image 5.

  Markers near the nested genes G72 and G30 on chromosome 13q33 have been implicated in the etiology of schizophrenia and, recently, bipolar affective disorder (BPAD). Hattori et al (2003) reportedMarkers near the nested genes G72 and G30 on chromosome 13q33 have been implicated in the etiology of schizophrenia and, recently, bipolar affective disorder (BPAD). Hattori et al (2003) reported that single-nucleotide polymorphisms (SNPs) near the G72/G30 locus were associated with BPAD in a sample of 22 pedigrees, and that SNP haplotypes were associated in a second, larger sample of triads. The present study attempts to replicate this finding in an independent case-control sample. Six SNPs near the G72/G30 locus, including the most strongly associated markers in the previous study, were tested in 139 cases and 113 ethnically matched controls. Significant association was detected between BPAD and two adjacent SNPs (smallest P=0.007; global P=0.024). Haplotype analysis produced additional support for association (smallest P=0.004; global P=0.004). Analysis of 31 unlinked microsatellite markers detected no population stratification in the cases or controls studied. Although the associated alleles and haplotypes differ from those previously reported, these new results provide further evidence, in an independent sample, for an association between BPAD and genetic variation in the vicinity of the genes G72 and G30.

• Novel CAG/CTG repeat expansion mutations do not contribute to the genetic risk for most cases of bipolar disorder or schizophrenia.

  Authors: T Tsutsumi, S E Holmes, M G McInnis, A Sawa, C Callahan, J R DePaulo, C A Ross, L E DeLisi, R L Margolis

  American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics. 02/2004; 124B(1):15-9.

  The possible presence of anticipation in bipolar affective disorder and schizophrenia has led to the hypothesis that repeat expansion mutations could contribute to the genetic etiology of theseThe possible presence of anticipation in bipolar affective disorder and schizophrenia has led to the hypothesis that repeat expansion mutations could contribute to the genetic etiology of these diseases. Using the repeat expansion detection (RED) assay, we have systematically examined genomic DNA from 100 unrelated probands with schizophrenia and 68 unrelated probands with bipolar affective disorder for the presence of CAG/CTG repeat expansions. Our results show that 28% of the probands with schizophrenia and 30% of probands with bipolar disorder have a CAG/CTG repeat in the expanded range, but that each expansion could be explained by one of three nonpathogenic repeat expansions known to exist in the general population. We conclude that novel CAG/CTG repeat expansions are not a common genetic risk factor for bipolar disorder or schizophrenia.

• Trapping and sequence analysis of 1138 putative exons from human chromosome 18.

  Authors: H Chen, N Wang, Y Huo, P Sklar, D F MacKinnon, J B Potash, F J McMahon, S E Antonarakis, J Raymond DePaulo, C A Ross, M G McInnis

  Molecular psychiatry. 07/2003; 8(6):619-23.

  In a search for novel genes on chromosome 18 (HC18), on which several regions have been linked to bipolar disorder, we applied exon trapping to HC18-specific cosmids. Among the 1138 exons trapped,In a search for novel genes on chromosome 18 (HC18), on which several regions have been linked to bipolar disorder, we applied exon trapping to HC18-specific cosmids. Among the 1138 exons trapped, 1052 of them have been mapped to HC18, and the remaining 86 have not been localized. No exons were localized to genomic regions other than HC18. BLAST database search revealed that 190 exons were identical to 98 Unigenes on HC18; 98 identical to additional 82 clusters of ESTs not present in the HC18 Unigene set; 39 homologous to genes from human and other species (e<10(-3)); and the remaining 811 exons had no significant homology to transcripts in public databases. The mapped exons were compared to the 867 annotated genes on HC18 in the Celera databases; 216 exons were identical to 104 Celera 'genes' and the remaining 836 exons were not found in the Celera databases. On average, there were two exons for a matched transcript (known genes and ESTs). Therefore, the 850 novel exons may represent hundreds of novel genes on chromosome 18.

• Genome-wide scan of bipolar disorder in 65 pedigrees: supportive evidence for linkage at 8q24, 18q22, 4q32, 2p12, and 13q12.

  Authors: M G McInnis, T H Lan, V L Willour, F J McMahon, S G Simpson, A M Addington, D F MacKinnon, J B Potash, A T Mahoney, J Chellis [......] K R Jamison, P Holmans, S E Folstein, K Ranade, C Friddle, D Botstein, T Marr, T H Beaty, P Zandi, J Raymond DePaulo

  Molecular psychiatry. 03/2003; 8(3):288-98.

  The purpose of this study was to assess 65 pedigrees ascertained through a Bipolar I (BPI) proband for evidence of linkage, using nonparametric methods in a genome-wide scan and for possible parentThe purpose of this study was to assess 65 pedigrees ascertained through a Bipolar I (BPI) proband for evidence of linkage, using nonparametric methods in a genome-wide scan and for possible parent of origin effect using several analytical methods. We identified 15 loci with nominally significant evidence for increased allele sharing among affected relative pairs. Eight of these regions, at 8q24, 18q22, 4q32, 13q12, 4q35, 10q26, 2p12, and 12q24, directly overlap with previously reported evidence of linkage to bipolar disorder. Five regions at 20p13, 2p22, 14q23, 9p13, and 1q41 are within several Mb of previously reported regions. We report our findings in rank order and the top five markers had an NPL>2.5. The peak finding in these regions were D8S256 at 8q24, NPL 3.13; D18S878 at 18q22, NPL 2.90; D4S1629 at 4q32, NPL 2.80; D2S99 at 2p12, NPL 2.54; and D13S1493 at 13q12, NPL 2.53. No locus produced statistically significant evidence for linkage at the genome-wide level. The parent of origin effect was studied and consistent with our previous findings, evidence for a locus on 18q22 was predominantly from families wherein the father or paternal lineage was affected. There was evidence consistent with paternal imprinting at the loci on 13q12 and 1q41.

• Genetic analysis of the (CTG)n NOTCH4 polymorphism in 65 multiplex bipolar pedigrees.

  Authors: T Swift-Scanlan, T H Lan, M D Fallin, J M Coughlin, J B Potash, J R DePaulo, M G McInnis

  Psychiatric genetics. 04/2002; 12(1):43-7.

  A strong genetic association between the NOTCH4 locus on chromosome 6 and schizophrenia was recently reported. Based on the data suggesting overlapping susceptibility for schizophrenia and bipolarA strong genetic association between the NOTCH4 locus on chromosome 6 and schizophrenia was recently reported. Based on the data suggesting overlapping susceptibility for schizophrenia and bipolar disorder, we genotyped the polymorphic (CTG)n encoding polyleucine repeat in exon 1 of NOTCH4 in 65 pedigrees ascertained for a genetic linkage study of bipolar disorder. In addition, we analyzed a subset of our pedigrees with psychotic features at this locus. We failed to find any association between the (CTG)n NOTCH4 polymorphism and either the bipolar or the psychotic bipolar phenotype in our 65 pedigrees.

• Family-based association study of 76 candidate genes in bipolar disorder: BDNF is a potential risk locus. Brain-derived neutrophic factor.

  Authors: P Sklar, S B Gabriel, M G McInnis, P Bennett, Y M Lim, G Tsan, S Schaffner, G Kirov, I Jones, M Owen, N Craddock, J R DePaulo, E S Lander

  Molecular psychiatry. 01/2002; 7(6):579-93.

  Identification of the genetic bases for bipolar disorder remains a challenge for the understanding of this disease. Association between 76 candidate genes and bipolar disorder was tested byIdentification of the genetic bases for bipolar disorder remains a challenge for the understanding of this disease. Association between 76 candidate genes and bipolar disorder was tested by genotyping 90 single-nucleotide polymorphisms (SNPs) in these genes in 136 parent-proband trios. In this preliminary analysis, SNPs in two genes, brain-derived neurotrophic factor (BDNF) and the alpha subunit of the voltage-dependent calcium channel were associated with bipolar disorder at the P<0.05 level. In view of the large number of hypotheses tested, the two nominally positive associations were then tested in independent populations of bipolar patients and only BDNF remains a potential risk gene. In the replication samples, excess transmission of the valine allele of amino acid 66 of BDNF was observed in the direction of the original result in an additional sample of 334 parent-proband trios (T/U=108/87, P=0.066). Resequencing of 29 kb surrounding the BDNF gene identified 44 additional SNPs. Genotyping eight common SNPs identified three additional markers transmitted to bipolar probands at the P < 0.05 level. Strong LD was observed across this region and all adjacent pairwise haplotypes showed excess transmission to the bipolar proband. Analysis of these haplotypes using TRANSMIT revealed a global P value of 0.03. A single haplotype was identified that is shared by both the original dataset and the replication sample that is uniquely marked by both the rare A allele of the original SNP and a novel allele 11.5 kb 3'. Therefore, this study of 76 candidate genes has identified BDNF as a potential risk allele that will require additional study to confirm.

• NEDD4L on human chromosome 18q21 has multiple forms of transcripts and is a homologue of the mouse Nedd4-2 gene.

  Authors: H Chen, C A Ross, N Wang, Y Huo, D F MacKinnon, J B Potash, S G Simpson, F J McMahon, J R DePaulo Jr, M G McInnis

  European journal of human genetics : EJHG. 01/2002; 9(12):922-30.

  The validation of full-length cDNA represents a crucial step in gene identification and subsequent functional analysis. In searching for candidate genes for bipolar disorder on chromosome 18q21, aThe validation of full-length cDNA represents a crucial step in gene identification and subsequent functional analysis. In searching for candidate genes for bipolar disorder on chromosome 18q21, a novel gene homologous to NEDD4 (Neural precursor cells expressed developmentally down-regulated) was identified using exon trapping and cDNA cloning. This novel gene is termed NEDD4L (Human Gene Nomenclature Committee symbol). Typical NEDD4 orthologues that contain a C2 (Ca(2+)/lipid-binding) and a HECT (Homologous to the E6-AP Carboxyl Terminus) ubiquitin-protein ligase domain, and multiple WW domains have been shown to regulate the epithelial sodium channel (ENaC). In mice, Nedd4 has two distinct isoforms termed Nedd4-1 that belongs to the typical NEDD4 class, and Nedd4-2 that is homologous to Nedd4-1 but lacks the C2 domain. NEDD4L contains the WW and HECT domains seen in the NEDD4 gene family, but lacks the C2 domain in the N-terminus. BLAST database search showed that the deduced polypeptide of NEDD4L has 97 and 62% sequence identity to mouse Nedd4-2 and human NEDD4, respectively. Multiple forms of transcripts of NEDD4L have been isolated, which differ in transcription start and termination sites together with the presence or absence of an alternative spliced exon. Northern blot analysis showed a 3.4 kb mRNA species was specifically expressed in heart and skeletal muscle, while a 3.2 kb band and/or an additional 3.6 kb band is seen in other tissues tested. Striking homology of NEDD4L to mouse Nedd4-2 suggests it is the human homologue of mouse Nedd4-2. Its position in a region of linkage for autosomal dominant orthostatic hypotensive disorder and its potential role in regulating ENaC make NEDD4L a candidate gene for this disorder.

• Linkage of bipolar disorder to chromosome 18q and the validity of bipolar II disorder.

  Authors: F J McMahon, S G Simpson, M G McInnis, J A Badner, D F MacKinnon, J R DePaulo

  Archives of general psychiatry. 12/2001; 58(11):1025-31.

  BACKGROUND: An analysis of the relationship between clinical features and allele sharing could clarify the issue of genetic linkage between bipolar affective disorder (BPAD) and chromosome 18q,BACKGROUND: An analysis of the relationship between clinical features and allele sharing could clarify the issue of genetic linkage between bipolar affective disorder (BPAD) and chromosome 18q, contributing to the definition of genetically valid clinical subtypes. METHODS: Relatives ascertained through a proband who had bipolar I disorder (BPI) were interviewed by a psychiatrist, assigned an all-sources diagnosis, and genotyped with 32 markers on 18q21-23. Exploratory findings from the first 28 families (n = 247) were tested prospectively in an additional 30 families (n = 259), and the effect of confirmed findings on the linkage evidence was assessed. RESULTS: In exploratory analyses, paternal allele sharing on 18q21 was significantly (P =.03) associated with a diagnostic subtype, and was greatest in pairs where both siblings had bipolar II disorder (BPII). Prospective analysis confirmed the finding that BPII-BPII sibling pairs showed significantly (P =.016) greater paternal allele sharing. Paternal allele sharing across 18q21-23 was also significantly greater in families with at least one BPII-BPII sibling pair. In these families, multipoint affected sibling-pair linkage analysis produced a peak paternal lod score of 4.67 (1-lod confidence interval, 12 centimorgans [cM]) vs 1.53 (1-lod confidence interval, 44 cM) in all families. CONCLUSIONS: Affected sibling pairs with BPII discriminated between families who showed evidence of linkage to 18q, and families who did not. Families with a BPII sibling pair produced an increased lod score and improved linkage resolution. These findings, limited by the small number of BPII-BPII sibling pairs, strengthen the evidence of genetic linkage between BPAD and chromosome 18q, and provide preliminary support for BPII as a genetically valid subtype of BPAD.

• The familial aggregation of psychotic symptoms in bipolar disorder pedigrees.

  Authors: J B Potash, V L Willour, Y F Chiu, S G Simpson, D F MacKinnon, G D Pearlson, J R DePaulo, M G McInnis

  The American journal of psychiatry. 09/2001; 158(8):1258-64.

  OBJECTIVE: Symptomatic overlap between affective disorders and schizophrenia has long been noted. More recently, family and linkage studies have provided some evidence for overlapping geneticOBJECTIVE: Symptomatic overlap between affective disorders and schizophrenia has long been noted. More recently, family and linkage studies have provided some evidence for overlapping genetic susceptibility between bipolar disorder and schizophrenia. If shared genes are responsible for the psychotic manifestations of both disorders, these genes may result in clustering of psychotic symptoms in some bipolar disorder pedigrees. The authors tested this hypothesis in families ascertained for a genetic study of bipolar disorder. METHOD: Rates of psychotic symptoms-defined as hallucinations or delusions-during affective episodes were compared in families of 47 psychotic and 18 nonpsychotic probands with bipolar I disorder. The analysis included 202 first-degree relatives with major affective disorder. RESULTS: Significantly more families of psychotic probands than families of nonpsychotic probands (64% versus 28%) contained at least one relative who had affective disorder with psychotic symptoms. Significantly more affectively ill relatives of psychotic probands than of nonpsychotic probands (34% versus 11%) had psychotic symptoms. An analysis of clustering of psychotic subjects across all families revealed significant familial aggregation. Clustering of psychosis was also apparent when only bipolar I disorder was considered the affected phenotype. CONCLUSIONS: Psychotic bipolar disorder may delineate a subtype of value for genetic and biological investigations. Families with this subtype should be used to search for linkage in chromosomal regions 10p12-13, 13q32, 18p11.2, and 22q11-13, where susceptibility genes common to bipolar disorder and schizophrenia may reside. Putative schizophrenia-associated biological markers, such as abnormal evoked response, oculomotor, and neuroimaging measures, could similarly be explored in such families.

• Attempted suicide and alcoholism in bipolar disorder: clinical and familial relationships.

  Authors: J B Potash, H S Kane, Y F Chiu, S G Simpson, D F MacKinnon, M G McInnis, F J McMahon, J R DePaulo

  The American journal of psychiatry. 01/2001; 157(12):2048-50.

  OBJECTIVE: This study examined the clinical and familial relationships between comorbid alcoholism and attempted suicide in affectively ill relatives of probands with bipolar I disorder. METHOD: InOBJECTIVE: This study examined the clinical and familial relationships between comorbid alcoholism and attempted suicide in affectively ill relatives of probands with bipolar I disorder. METHOD: In 71 families ascertained for a genetic linkage study, 337 subjects with major affective disorder were assessed by using the Schedule for Affective Disorders and Schizophrenia-Lifetime Version. RESULTS: Subjects with bipolar disorder and alcoholism had a 38.4% lifetime rate of attempted suicide, whereas those without alcoholism had a 21.7% rate. Attempted suicide among subjects with bipolar disorder and alcoholism clustered in a subset of seven families. Families with alcoholic and suicidal probands had a 40.7% rate of attempted suicide in first-degree relatives with bipolar disorder, whereas other families had a 19.0% rate. CONCLUSIONS: Comorbid alcoholism was associated with a higher rate of attempted suicide among family members with bipolar disorder. Attempted suicide and alcoholism clustered in a subset of families. These relationships may have a genetic origin and may be mediated by intoxication, mixed states, and/or temperamental instability.

• Gene identification using exon amplification on human chromosome 18q21: implications for bipolar disorder.

  Authors: H Chen, Y Huo, S Patel, X Zhu, T Swift-Scanlan, R H Reeves, R DePaulo, C A Ross, M G McInnis

  Molecular psychiatry. 09/2000; 5(5):502-9.

  We previously reported linkage between bipolar disorder and a region on human chromosome (HC) 18q21. To identify genes in this region, exon trapping was performed on cosmids isolated from anWe previously reported linkage between bipolar disorder and a region on human chromosome (HC) 18q21. To identify genes in this region, exon trapping was performed on cosmids isolated from an HC18-specific cosmid library (LL18NC02) using 47 sequence tagged site (STS) markers from 18q21 as hybridization probes. A total of 285 unique sequences (exons) were obtained from 850 sequenced clones. Homology searching of the databases using NCBI's BLAST algorithms revealed that 31 exons have identity to known genes and/or ESTs, seven are identical to regions of finished genomic sequences in the 18q21 region, 20 have significant similarity (>30% sequence identity) to genes from human and/or other species, 19 were repetitive sequences, and 208 sequences (72%) are novel. Seventy per cent of the trapped sequences were predicted to be derived from genes using library screening and RT-PCR analyses. This represents an initial stage in characterizing genes in a susceptibility region for further study in bipolar disorder or other diseases that map to this region.

• Psychiatric epigenetics: a new focus for the new century.

  Authors: A Petronis, I I Gottesman, T J Crow, L E DeLisi, A J Klar, F Macciardi, M G McInnis, F J McMahon, A D Paterson, D Skuse, G R Sutherland

  Molecular psychiatry. 08/2000; 5(4):342-6.

• Allelic distribution of CTG18.1 in Caucasian populations: association studies in bipolar disorder, schizophrenia, and ataxia.

  Authors: M G McInnis, T Swift-Scanlanl, A T Mahoney, J Vincent, G Verheyen, T H Lan, L Oruc, O Riess, C Van Broeckhoven, H Chen, J L Kennedy, D F MacKinnon, R L Margolis, S G Simpson, F J McMahon, E Gershon, J Nurnberger, T Reich, J R DePaulo, C A Ross

  Molecular psychiatry. 08/2000; 5(4):439-42.

  CTG18.1 is a highly polymorphic and unstable CTG repeat within an intron of the SEF2-1 gene. We tested the CTG18.1 repeat length in affective disorder, schizophrenia, and nonspecific ataxia; theseCTG18.1 is a highly polymorphic and unstable CTG repeat within an intron of the SEF2-1 gene. We tested the CTG18.1 repeat length in affective disorder, schizophrenia, and nonspecific ataxia; these diseases all have shown clinical evidence for anticipation. There was no difference in the allele frequencies comparing the controls and disease groups. The most common allele contains 11 CAGs (35%) followed by alleles with 14-17 CAGs (35%). There was no difference in the distribution of the alleles in the cases vs controls for ataxia (P = 0.11), affective disorders (P = 0.21), or schizophrenia (P = 0.26). The frequency of unstable CTG18.1 alleles was approximately 3% in a population of N. European descent and is not related to the phenotypes tested.

• Anticipation in schizophrenia: a review and reconsideration.

  Authors: M G McInnis, F J McMahon, T Crow, C A Ross, L E DeLisi

  American journal of medical genetics. 01/2000; 88(6):686-93.

  There have been several reports on anticipation and schizophrenia, and the purpose of the present article is to review the literature and present data from an ongoing family study of schizophrenia.There have been several reports on anticipation and schizophrenia, and the purpose of the present article is to review the literature and present data from an ongoing family study of schizophrenia. The published data find on average a 10-year difference in the age of onset between the parental and offspring generation in family sets that have been ascertained for a genetic linkage study. The biases inherent in such studies include the biases of ascertainment that were described by Penrose [1948]. Several investigators have searched for evidence of enlarged triplet repeats, and some find evidence consistent with expanded triplet repeats, whereas others do not. In any event the phenomenon of anticipation in schizophrenia appears to be consistently found and an explanation is needed. Data are presented from pairwise analyses using intergenerational pairs from 61 pedigrees with schizophrenia showing evidence of anticipation as well as the fertility bias. Anticipation was found in aunt:niece/nephew pairs (14.5 years) but not in uncle:niece/nephew pairs (0.5 years). The sex difference in age of onset was accentuated in uncles versus aunts (8.5 years), present in parents (4.5 years), but absent in the proband generation. Therefore, there appears to be an interaction within families between age of onset and sex that deserves further investigation. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:686-693, 1999.

• Expansion of a novel CAG trinucleotide repeat in the 5' region of PPP2R2B is associated with SCA12.

  Authors: S E Holmes, E E O'Hearn, M G McInnis, D A Gorelick-Feldman, J J Kleiderlein, C Callahan, N G Kwak, R G Ingersoll-Ashworth, M Sherr, A J Sumner, A H Sharp, U Ananth, W K Seltzer, M A Boss, A M Vieria-Saecker, J T Epplen, O Riess, C A Ross, R L Margolis

  Nature genetics. 01/2000; 23(4):391-2.