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Melvin G McInnis

Publications and source records attributed to Melvin G McInnis.

At least 19 recordsLinked to original sources
PubMed2026

Genomic dimensions deconstruct the clinical heterogeneity of bipolar disorder.

Bipolar disorder's (BD) clinical heterogeneity has an unresolved genetic basis. We meta-analyzed genome-wide association studies (GWAS) of 16 BD subphenotypes in 226,032 individuals from 57 cohorts (38,022 cases); 10 advanced to multivariate and multi-trait analyses. Four factors (compulsive, psychotic, dysregulated, internalizing) explained 82.8% of shared genetic variance. BD1 and BD2 loaded on distinct factors despite a high genetic correlation; 87.0% of common-factor loci were significant in neither subtype. Unipolar mania aligned with psychosis over internalizing, and was distinguishable from BD1, and rapid cycling showed heritable cross-domain liability. We identified 356 risk loci, 158 novel, including the first univariate-GWAS associations for psychosis, unipolar mania, rapid cycling and schizoaffective disorder-and 249 credible genes (89 high-confidence), 12 with approved-drug or clinical-phase annotations. Cell-type association showed a midbrain dopaminergic-GABAergic gradient along the psychotic factor. BD's genetic architecture appears hierarchical-a general liability resolving into dimensions of course and comorbidity, beyond subtypes.

Journal Article↗
PubMed2018

Chronotype and cellular circadian rhythms predict the clinical response to lithium maintenance treatment in patients with bipolar disorder.

Bipolar disorder (BD) is a serious mood disorder associated with circadian rhythm abnormalities. Risk for BD is genetically encoded and overlaps with systems that maintain circadian rhythms. Lithium is an effective mood stabilizer treatment for BD, but only a minority of patients fully respond to monotherapy. Presently, we hypothesized that lithium-responsive BD patients (Li-R) would show characteristic differences in chronotype and cellular circadian rhythms compared to lithium non-responders (Li-NR). Selecting patients from a prospective, multi-center, clinical trial of lithium monotherapy, we examined morning vs. evening preference (chronotype) as a dimension of circadian rhythm function in 193 Li-R and Li-NR BD patients. From a subset of 59 patient donors, we measured circadian rhythms in skin fibroblasts longitudinally over 5 days using a bioluminescent reporter (Per2-luc). We then estimated circadian rhythm parameters (amplitude, period, phase) and the pharmacological effects of lithium on rhythms in cells from Li-R and Li-NR donors. Compared to Li-NRs, Li-Rs showed a difference in chronotype, with higher levels of morningness. Evening chronotype was associated with increased mood symptoms at baseline, including depression, mania, and insomnia. Cells from Li-Rs were more likely to exhibit a short circadian period, a linear relationship between period and phase, and period shortening effects of lithium. Common genetic variation in the IP3 signaling pathway may account for some of the individual differences in the effects of lithium on cellular rhythms. We conclude that circadian rhythms may influence response to lithium in maintenance treatment of BD.

Adult↗
PubMed2006

A comparison of the familiality of chronic depression in recurrent early-onset depression pedigrees using different definitions of chronicity.

BACKGROUND: The study of chronicity in the course of major depression has been complicated by varying definitions of this illness feature. Because familial clustering is one component of diagnostic validity we compared family clustering of chronicity as defined in the DSM-IV to that of chronicity determined by an assessment of lifetime course of depressive illness. METHODS: In 1750 affected subjects from 652 families recruited for a genetic study of recurrent, early-onset depression, we applied several definitions of chronicity. Odds ratios were determined for the likelihood of chronicity in a proband predicting chronicity in an affected relative. RESULTS: There was greater family clustering of chronicity as determined by assessment of lifetime course (OR=2.54) than by DSM-IV defined chronic major depressive episode (MDE) (OR=1.93) or dysthymic disorder (OR=1.76). In families with probands who had preadolescent onset of MDD, familiality was increased by all definitions, with a much larger increase observed for chronicity by lifetime course (ORs were 6.14 for lifetime chronicity, 2.43 for chronic MDE, and 3.42 for comorbid dysthymic disorder). Agreement between these definitions of chronicity was only fair. LIMITATIONS: The data used to determine chronicity were collected retrospectively and not blindly to relatives' status, and assessment of lifetime course was based on global clinical impressions gathered during a semi-structured diagnostic interview. Also, it can be difficult to determine whether individuals with recurrent major depressive episodes who frequently experience long periods of low grade depressive symptoms meet the strict timing requirements of DSM-IV dysthymic disorder. CONCLUSIONS: An assessment of lifetime symptom course identifies a more familial, and thus possibly a more valid, type of chronic depression than the current DSM-IV categories which are defined in terms of particular cross-sectional features of illness.

Adolescent↗
PubMed2006

Attempted suicide in bipolar disorder pedigrees: evidence for linkage to 2p12.

BACKGROUND: We are interested in identifying susceptibility genes that predispose subjects to attempted suicide. METHODS: We conducted a secondary analysis of genome-wide linkage data from 162 bipolar pedigrees that incorporated attempted suicide as a clinical covariate. RESULTS: The strongest covariate-based linkage signal was seen on 2p12 at marker D2S1777. The logarithm of odds (LOD) score at marker D2S1777 rose from 1.56 to 3.82 after inclusion of the suicide covariate, resulting in significant chromosome-wide empirically derived p-values for the overall linkage finding (p = .01) and for the change in LOD score after the inclusion of the covariate (p = .02). CONCLUSIONS: The finding on chromosome 2 replicates results from two previous studies of attempted suicide in pedigrees with alcohol dependence and in pedigrees with recurrent early-onset depression. Combined, these three studies provide compelling evidence for a locus influencing attempted suicide on 2p12.

Bipolar Disorder↗
PubMed2006

Reproductive cycle-associated mood symptoms in women with major depression and bipolar disorder.

BACKGROUND: We sought to determine the prevalence of, and association between, reproductive cycle-associated mood symptoms in women with affective disorders. We hypothesized that symptoms would correlate with each other across a woman's reproductive life span in both major depression (MDD) and bipolar I disorder (BP). METHODS: 2412 women with, MDD or BP were asked standardized questions about mood symptoms prior to menstruation, within a month of childbirth and during perimenopause. Lifetime rates for each of these symptom types were determined and an odds ratio was calculated correlating each of the types with the others. RESULTS: Of 2524 women with mood disorders, 67.7% reported premenstrual symptoms. Of those at risk, 20.9% reported postpartum symptoms and 26.4% reported perimenopausal symptoms. The rates did not differ between women with MDD and BP but were significantly different from women who were never ill. The symptoms were significantly correlated in women with MDD with odds ratios from 1.66 to 1.82, but were not in women with BP. LIMITATIONS: This is a secondary analysis of a sample that was collected for other purposes and is based upon retrospective reporting. CONCLUSIONS: Reproductive cycle-associated mood symptoms were commonly reported in women with mood disorders and did not differ based on diagnosis. In MDD, but not BP, the occurrence of these symptoms was trait-like as the presence of one predicted the occurrence of the others. Further prospective study is required to clarify the determinants of this trait.

Adult↗
PubMed2006

Differential expression of disrupted-in-schizophrenia (DISC1) in bipolar disorder.

BACKGROUND: The disruption of the disrupted-in-schizophrenia (DISC1) gene segregates with major mental illnesses in a Scottish family. Association of DISC1 with schizophrenia has been reported in several ethnic groups, and now recently with mood disorder. METHODS: A family-based association study of DISC1 and bipolar disorder (BP) in 57 bipolar pedigrees was conducted. Then, we examined possible association of bipolar disorder with DISC1 mRNA expression in human lymphoblasts. We also studied the correlation of several clinical features with the levels of DISC1 mRNA expression. RESULTS: Haplotype analysis identified one haplotype (HP1) that was overtransmitted to the BP phenotype (p = .01) and a second haplotype that was undertransmitted (HP2). There was a gender influence in the transmission distortion, with overtransmission of HP1 to affected females (p = .004). A significant decrease in DISC1 mRNA expression was observed in lymphoblasts from affected HP1 group compared to those from unaffected subjects with the HP2 (p = .006). Further, a higher number of manic symptoms correlated with lower levels of DISC1 expression (p = .008). CONCLUSIONS: These results suggest that decreased mRNA levels of DISC1 expression, associating with the risk haplotype, may be implicated in the pathophysiology of bipolar disorder.

Bipolar Disorder↗
PubMed2006

Familial aggregation of illness chronicity in recurrent, early-onset major depression pedigrees.

OBJECTIVE: The authors used a large sample collected for genetic studies to determine whether a chronic course of illness defines a familial clinical subtype in major depressive disorder. METHOD: A measure of lifetime chronicity of depressive symptoms (substantial mood symptoms most or all of the time) was tested for familial aggregation in 638 pedigrees from the Genetics of Recurrent Early-Onset Depression (GenRED) project. RESULTS: In subjects with chronic depression, the mean age at illness onset was lower and rates of attempted suicide, panic disorder, and substance abuse were higher than among those with nonchronic depression. Chronicity was assessed in 37.8% of affected first-degree relatives of probands with chronic depression and in 20.2% of relatives of probands with nonchronic depression. Analysis using the generalized estimating equation model yielded an odds ratio of 2.52 (SE=0.39, z=6.02, p<0.0001) for the likelihood of chronicity in a proband predicting chronicity in an affected relative. With stratification by proband age at illness onset, the odds ratio for chronicity in relatives by proband chronicity status was 6.17 (SE=2.09, z=5.35, p<0.0001) in families of probands whose illness onset was before age 13 and 1.92 (SE=0.34, z=3.72, p<0.0001) in families of probands whose illness started at age 13 or later. CONCLUSIONS: These findings suggest that chronicity of depressive symptoms is familial, especially in preadolescent-onset illness. Chronicity is also associated with other indicators of illness severity in recurrent, early-onset major depression. Further study using chronicity as a subtype in the genetic analysis of depressive illness is warranted. Refinement of the definition of chronicity in depressive illness may increase the power of such studies.

Adolescent↗
PubMed2006

Clinical correlates and familial aggregation of age at onset in bipolar disorder.

OBJECTIVE: To assess whether age at onset variation reflects underlying genetic heterogeneity in bipolar disorder, the authors examined the clinical and familial characteristics of age at onset in bipolar disorder subjects from families with multiple affected members. METHOD: A total of 211 families with 1,856 subjects were ascertained through bipolar I disorder probands. All the subjects were assessed with the Diagnostic Interview for Genetic Studies and assigned diagnoses by trained clinicians using best estimate procedures. Admixture analysis with the 211 bipolar disorder probands was used to decompose the age-at-onset distribution into a mixture of theoretical normal distributions. Logistic regression with general estimating equations was then used to examine clinical correlates and familial aggregation of age at onset in all 717 bipolar disorder subjects. RESULTS: The age-at-onset distribution consisted of a mixture of three normal distributions with means of 16.6 (SD=5.1), 26.0 (SD=1.4), and 34.7 (SD=6.6) years that comprised 79.7%, 7.2%, and 13.1% of the group, respectively. Cutoff points at ages 21 and 28 were derived from this analysis and used to define age-at-onset subgroups. Early-onset (age at onset </=21) subjects had higher risks of drug abuse, alcohol abuse, rapid cycling, and suicide attempts. Affected subjects from a family with an early-onset proband were more likely than others to have an early onset (odds ratio=4.53, 95% CI=3.09-6.64). Subjects from a family with a proband whose age at onset was <28 were also more likely to have higher risks of drug abuse (odds ratio=11.62, 95% CI=2.16-62.66). CONCLUSIONS: Age at onset is associated with clinical heterogeneity in bipolar disorder and aggregates, possibly along with drug abuse, within families. These findings are consistent with the conclusion that age at onset reflects underlying genetic heterogeneity in bipolar disorder. Thus, age at onset may conceivably be used to identify more homogeneous groups of bipolar disorder families and thereby facilitate the mapping of bipolar disorder susceptibility genes.

Adult↗
PubMed2005

Is perinatal depression familial?

BACKGROUND: While major depressive disorder (MDD) is familial, it is not clear whether distinct familial-genetic factors influence vulnerability to depression during or after pregnancy. Here we examine familial aggregation of perinatal major depression (PND, any episode during pregnancy or the month after childbirth) and the subset of post-partum depression (PPD) in families with multiple cases of recurrent, early-onset MDD from the Genetics of Recurrent Early-Onset Depression dataset. METHODS: The dataset included 691 childbearing women who could be classified as PND (27.6%) or non-PND (NPND), of whom 328 were members of 148 sibships with two or more PND or NPND women. PND and NPND subjects were compared for differences in putative predictors. Prediction of sibling PND or PPD by the proband's history was examined using logistic regression and general estimating equation methods. RESULTS: PND was associated with fewer episodes and younger current age. Odds ratios for prediction of sibling status were significant for PND (2.28) and PPD (3.96), particularly when current age was under 46 (2.87 and 4.39, respectively). ORs for PPD were not significantly different from those for PND. The OR for PPD (3.52), but not for PND, remained significant after current age was introduced as a covariate, but not when both current age and number of episodes were included in the model. LIMITATIONS: Because detailed data were not collected for all pregnancies, we cannot determine whether current age and number of episodes mediated the observed effects due to recall bias or other factors (cohort effect, number of episodes). CONCLUSIONS: A familial component to PND, and particularly PPD, is suggested by the results. However more systematic study is needed to confirm this result. A greater understanding of both genetic and non-genetic familial factors could lead to improved prevention and clinical management.

Adult↗
PubMed2005

Assessment of the effect of age at onset on linkage to bipolar disorder: evidence on chromosomes 18p and 21q.

Previous evidence suggests that the inheritance of bipolar disorder (BP) may vary depending on the age at onset (AAO). Therefore, we sought to incorporate AAO as a covariate in linkage analyses of BP using two different methods, LODPAL and ordered-subset analysis (OSA), in genomewide scans of 150 multiplex pedigrees with 874 individuals. The LODPAL analysis identified two loci, on chromosomes 21q22.13 (LOD = 3.29; empirical chromosomewide P value = .009) and 18p11.2 (LOD = 2.83; empirical chromosomewide P = .05), with increased linkage among subjects who had early onset (AAO < or = 21 years) and later onset (AAO >21 years), respectively. The finding on 21q22.13 was significant at the chromosomewide level, even after correction for multiple testing. Moreover, a similar finding was observed in an independent sample of 65 pedigrees (LOD = 2.88; empirical chromosomewide P = .025). The finding on 18p11.2 was only nominally significant and was not observed in the independent sample. However, 18p11.2 emerged as one of the strongest regions in the OSA (LOD = 2.92; empirical P = .001), in which it was the only finding to meet chromosomewide levels of significance after correction for multiple testing. These results suggest that 21q22.13 and 18p11.2 may harbor genes that increase the risks for early-onset and later-onset forms of BP, respectively. There have been previous reports of linkage on 21q22.13 and 18p11.2, but the findings have not been consistent. This inconsistency may be due to differences in the AAO characteristics of the samples examined. Future studies to fine map susceptibility genes for BP on chromosomes 21q22.13 and 18p11.2 should take AAO into account.

Age of Onset↗
PubMed2005

Combined analysis from eleven linkage studies of bipolar disorder provides strong evidence of susceptibility loci on chromosomes 6q and 8q.

Several independent studies and meta-analyses aimed at identifying genomic regions linked to bipolar disorder (BP) have failed to find clear and consistent evidence of linkage regions. Our hypothesis is that combining the original genotype data provides benefits of increased power and control over sources of heterogeneity that outweigh the difficulty and potential pitfalls of the implementation. We conducted a combined analysis using the original genotype data from 11 BP genomewide linkage scans comprising 5,179 individuals from 1,067 families. Heterogeneity among studies was minimized in our analyses by using uniform methods of analysis and a common, standardized marker map and was assessed using novel methods developed for meta-analysis of genome scans. To date, this collaboration is the largest and most comprehensive analysis of linkage samples involving a psychiatric disorder. We demonstrate that combining original genome-scan data is a powerful approach for the elucidation of linkage regions underlying complex disease. Our results establish genomewide significant linkage to BP on chromosomes 6q and 8q, which provides solid information to guide future gene-finding efforts that rely on fine-mapping and association approaches.

Bipolar Disorder↗
PubMed2005

Characterization of CTG/CAG repeats on chromosome 18: a study of bipolar disorder.

Anticipation has been frequently found in bipolar families ascertained for linkage studies. An association of polymorphic triplet repeats with the bipolar phenotype in some pedigrees has been proposed. We have previously found linkage to chromosome 18 in a set of families with evidence of anticipation. As part of a search for CAG/CTG motifs on chromosome 18, we screened a genomic chromosome 18 cosmid library and identified 65 loci with trinucleotide repeats. Eleven of 33 genotyped loci were polymorphic, though none of these showed any evidence of instability. We performed genetic analysis of six loci in the Hopkins/Dana bipolar pedigrees ascertained for a genetic linkage study of bipolar disorder and found that the CAG repeat within the AD4D2 clone on 18q21.1 showed nominally significant over-transmission of the rare CAG23 allele (P=0.034). We have characterized all 65 trinucleotide repeats and flanking sequences with GENSCAN analysis and find that 29 were predicted to be in coding regions. These 29 trinucleotide-repeat-containing genes may be involved in functional modulation of their respective proteins, and may be candidates for other diseases or disease mechanisms that map to this region.

Animals↗
PubMed2004

Loci on chromosomes 6q and 6p interact to increase susceptibility to bipolar affective disorder in the national institute of mental health genetics initiative pedigrees.

BACKGROUND: We have reported genetic linkage between bipolar disorder and markers on chromosome 6q16.3-22.1 in the National Institute of Mental Health Genetics Initiative wave 3 pedigrees. Here we test for: 1) robustness of the linkage to differing analysis methods, genotyping error, and gender-specific maps; 2) parent-of-origin effects; and 3) interaction with markers within the schizophrenia linkage region on chromosome 6p. METHODS: Members of 245 families ascertained through a sibling pair affected with bipolar I or schizoaffective-bipolar disorder were genotyped with 18 markers spanning chromosome 6. Nonparametric linkage analysis was performed. RESULTS: Linkage to 6q is robust to analysis method, gender-specific map differences, and genotyping error. The locus confers a 1.4-fold increased risk. Affected siblings share the maternal more often than the paternal chromosome (p =.006), which could reflect a maternal parent-of-origin effect. There is a positive correlation between family-specific linkage scores on 6q and those on 6p22.2 (r =.26; p <.0001). Linkage analysis for each locus conditioned on evidence of linkage to the other increases the evidence for linkage at both loci (p <.0005). Logarithm of the odds (LOD) scores increased from 2.26 to 5.42 on 6q and from.35 to 2.26 on 6p22.2. CONCLUSIONS: These results support linkage of bipolar disorder to 6q, uncover a maternal parent-of-origin effect, and demonstrate an interaction of this locus with one on chromosome 6p22.2, previously linked only to schizophrenia.

Bipolar Disorder↗
PubMed2004

Genomewide significant linkage to recurrent, early-onset major depressive disorder on chromosome 15q.

A genome scan was performed on the first phase sample of the Genetics of Recurrent Early-Onset Depression (GenRED) project. The sample consisted of 297 informative families containing 415 independent affected sibling pairs (ASPs), or, counting all possible pairs, 685 informative affected relative pairs (555 ASPs and 130 other pair types). Affected cases had recurrent major depressive disorder (MDD) with onset before age 31 years for probands or age 41 years for other affected relatives; the mean age at onset was 18.5 years, and the mean number of depressive episodes was 7.3. The Center for Inherited Disease Research genotyped 389 microsatellite markers (mean spacing of 9.3 cM). The primary linkage analysis considered allele sharing in all possible affected relative pairs with the use of the Z(lr) statistic computed by the ALLEGRO program. A secondary logistic regression analysis considered the effect of the sex of the pair as a covariate. Genomewide significant linkage was observed on chromosome 15q25.3-26.2 (Zlr=4.14, equivalent LOD = 3.73, empirical genomewide P=.023). The linkage was not sex specific. No other suggestive or significant results were observed in the primary analysis. The secondary analysis produced three regions of suggestive linkage, but these results should be interpreted cautiously because they depended primarily on the small subsample of 42 male-male pairs. Chromosome 15q25.3-26.2 deserves further study as a candidate region for susceptibility to MDD.

Adolescent↗
PubMed2003

Genome-wide scan and conditional analysis in bipolar disorder: evidence for genomic interaction in the National Institute of Mental Health genetics initiative bipolar pedigrees.

BACKGROUND: In 1989 the National Institute of Mental Health began a collaborative effort to identify genes for bipolar disorder. The first 97 pedigrees showed evidence of linkage to chromosomes 1, 6, 7, 10, 16, and 22 (Nurnberger et al 1997). An additional 56 bipolar families have been genotyped, and the combined sample of 153 pedigrees studied. METHODS: Three hierarchical affection status models were analyzed with 513 simple sequence repeat markers; 298 were common across all pedigrees. The primary analysis was a nonparametric genome-wide scan. We performed conditional analyses based on epistasis or heterogeneity for five regions. RESULTS: One region, on 16p13, was significant at the genome-wide p <.05 level. Four additional chromosomal regions (20p12, 11p15, 6q24, and 10p12) showed nominally significant linkage findings (p </=.01). Conditional analysis assuming epistasis identified a significant increase in linkage at four regions. Families linked to 6q24 showed a significant increase in nonparametric logarithms of the odds (NPL) scores at 5q11 and 7q21. Epistasis also was observed between 20p12 and 13q21, and 16p13 and 9q21. CONCLUSIONS: The findings are presented in rank order of nominal significance. Several of these regions have been previously implicated in independent studies of either bipolar disorder or schizophrenia. The strongest finding is at 16p13 at D16S748 with an NPL of 3.3, there is evidence of epistasis between this locus and 9q21. Application of conditional analyses is potentially useful in larger sample collections to identify susceptibility genes of modest influence that may not be identified in a genome-wide scan aimed to identify single gene effects.

Bipolar Disorder↗
PubMed2003

Genome scan of the fifty-six bipolar pedigrees from the NIMH genetics initiative replication sample: chromosomes 4, 7, 9, 18, 19, 20, and 21.

The NIMH genetics initiative on bipolar disorder was established to collect uniformly ascertained bipolar pedigrees for genetic studies. In 1997, the four participating sites published a genome scan on the initial set of 97 bipolar pedigrees. Fifty-six additional bipolar pedigrees have now been ascertained and evaluated. This replication pedigree set contains 354 genotyped subjects, including 139 bipolar I (BPI) subjects, five schizoaffective bipolar type SA/BP subjects, 41 bipolar II (BPII) subjects, and 43 recurrent unipolar (RUP) depression subjects. Our site has recently genotyped the replication study bipolar pedigrees using 107 microsatellite markers from chromosomes 4, 7, 9, 18, 19, 20, and 21. We are now reporting parametric and nonparametric linkage results from this effort. Multipoint nonparametric linkage analysis produced three candidate regions with allele sharing LOD scores >/= 1.0. The linkage signal on 4q35 peaked between markers D4S3335 and D4S2390 with an allele sharing LOD score of 2.49. This finding exceeds standard criteria for suggestive linkage. Two additional loci approach suggestive linkage levels: the 4q32 finding had its maximum near marker D4S1629 with an allele sharing LOD score of 2.16, and the 20p12 finding peaked at D20S162 with an allele sharing LOD score of 1.82. Multipoint parametric linkage analysis produced similar findings. When we combined the genotype data from the original and the replication pedigree sets, 20p12 yielded a nonparametric LOD score of 2.38, which exceeds standard criteria for suggestive linkage, and a corresponding parametric HLOD score of 2.98. The combined analysis did not provide further support for linkage to 4q32 and 4q35.

Bipolar Disorder↗