Molecular Heterosis: A Review

Comings, David E.; MacMurray, James P.

doi:10.1006/mgme.2000.3015

Cited by 316 publications

(263 citation statements)

References 38 publications

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“…The model for the effect of R219K on APOB and CSF Ab 1-42 suggested by the above data implies either heterosis (Comings and MacMurray 2000) or a possible interaction with other variants in ABCA1 (or a nearby gene). To begin exploring this latter possibility in the CVD sample (since it affords the most power to detect such effects), genotyping of the I883M and R1587K variants was performed, and ANOVA used to model the potential independent main effects in a joint analysis of all three markers (including R219K).…”

Section: Resultsmentioning

confidence: 85%

Quantitative trait loci in ABCA1 modify cerebrospinal fluid amyloid-β1-42 and plasma apolipoprotein levels

Katzov

Bennet

Höglund³

et al. 2005

J Hum Genet

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The ATP-binding cassette transporter A1 encoded by ABCA1 plays an integral role in the efflux of cellular cholesterol and phospholipids, but may also be a central mediator of b-amyloid (Ab) processing. Here, genetic association of the common R219K variant of ABCA1 is shown with cerebrospinal fluid (CSF) Ab 1-42 levels, reinforcing emerging evidence of a connection between lipid and Ab metabolism. In support of this finding we demonstrate for the first time that CSF cholesterol and Ab 1-42 are correlated. To affirm the plausible impact of ABCA1 variation on cholesterol and related traits as well as to empower a survey of possible interactions (e.g. age, gender, and smoking), a large Swedish population consisting of over 2,700 individuals was enlisted and extensive measures of plasma lipid parameters carried out. These analyses revealed that R219K has a strong effect on apolipoprotein B (APOB) and LDLcholesterol (LDL-C) among smokers (P=0.000055 and P=0.00059, respectively), but not among non-smokers. In contrast, no effect was evident with apolipoprotein A (APOA1) or HDL-cholesterol (HDL-C) levels. Plasma APOB and LDL-C, but not APOA1 and HDL-C, were shown to be markedly elevated in smokers versus nonsmokers, affirming that smoking may selectively impact the former pathway. No other genetic markers in ABCA1 exhibit effects as large as R219K, although a modest independent effect of R1587K was observed. Our data illuminate a possible genetic link between Ab and cholesterol metabolism, but also provide an intriguing example of an environmental exposure that may modify a genotype-phenotype relationship.

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Section: Resultsmentioning

confidence: 85%

Quantitative trait loci in ABCA1 modify cerebrospinal fluid amyloid-β1-42 and plasma apolipoprotein levels

Katzov

Bennet

Höglund³

et al. 2005

J Hum Genet

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“…Alternatively, it is possible that this is an example of molecular heterosis, a common phenomenon that may be seen in as many as 50% of association studies. 51 A more complete assessment of this and the genetic associations that were observed among other cohorts await further investigation in the patient cohorts of other investigators, to establish whether there is wider support for FAT as a putative susceptibility gene.…”

Section: Discussionmentioning

confidence: 95%

Positional cloning, association analysis and expression studies provide convergent evidence that the cadherin gene FAT contains a bipolar disorder susceptibility allele

et al. 2006

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A susceptibility locus for bipolar disorder was previously localized to chromosome 4q35 by genetic linkage analysis. We have applied a positional cloning strategy, combined with association analysis and provide evidence that a cadherin gene, FAT, confers susceptibility to bipolar disorder in four independent cohorts (allelic P-values range from 0.003 to 0.024). In two case-control cohorts, association was identified among bipolar cases with a family history of psychiatric illness, whereas in two cohorts of parent-proband trios, association was identified among bipolar cases who had exhibited psychosis. Pooled analysis of the case-control cohort data further supported association (P = 0.0002, summary odds ratio = 2.31, 95% CI: 1.49-3.59). We localized the bipolar-associated region of the FAT gene to an interval that encodes an intracellular EVH1 domain, a domain that interacts with Ena/VASP proteins, as well as putative b-catenin binding sites. Expression of Fat, Catnb (b-catenin), and the three genes (Enah, Evl and Vasp) encoding the Ena/VASP proteins, were investigated in mice following administration of the mood-stabilizing drugs, lithium and valproate. Fat was shown to be significantly downregulated (P = 0.027), and Catnb and Enah were significantly upregulated (P = 0.0003 and 0.005, respectively), in response to therapeutic doses of lithium. Using a protein interaction map, the expression of genes encoding murine homologs of the FAT (ft)-interacting proteins was investigated. Of 14 interacting molecules that showed expression following microarray analysis (including several members of the Wnt signaling pathway), eight showed significantly altered expression in response to therapeutic doses of lithium (binomial P = 0.004). Together, these data provide convergent evidence that FAT and its protein partners may be components of a molecular pathway involved in susceptibility to bipolar disorder.

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“…The results of the additional analyses on three subsamples indicate that the chance of a false negative finding is minimal. Finally, it was considered that the significant v 2 test for DSM-IV major depression could indicate that there is no additive or dominance effect, but that a mechanism called negative heterosis plays a role (Comings and MacMurray 2000). Since the TDT models an additive effect, the absence of a significant result does not exclude the possibility of heterosis.…”

Section: Discussionmentioning

confidence: 99%

Family Based Association Analyses between the Serotonin Transporter Gene Polymorphism (5-HTTLPR) and Neuroticism, Anxiety and Depression

et al. 2007

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We studied the association between the short/long promotor-based length polymorphism of the serotonin transporter gene (5-HTTLPR) and neuroticism, anxiety and depression. Subjects included twins, their siblings and parents from the Netherlands Twin Register (559 parents and 1,245 offspring). Subjects had participated between one and five times in a survey study measuring neuroticism, anxiety and depression. Offspring of these families were also approached to participate in a psychiatric interview diagnosing DSM-IV major depression. Within-family and total association between 5-HTTLPR and these traits were tested. Only three of the 36 tests showed a significant effect of 5-HTTLPR (P < 0.05). These effects were in opposite directions, i.e. both negative and positive regression coefficients were found for the s allele. No additive effect of the s allele was found for DSM-IV depression. Our results strongly suggest that there is no straightforward association between 5-HTTLPR and neuroticism, anxiety and depression.

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Molecular Heterosis: A Review

Cited by 316 publications

References 38 publications

Quantitative trait loci in ABCA1 modify cerebrospinal fluid amyloid-β1-42 and plasma apolipoprotein levels

Quantitative trait loci in ABCA1 modify cerebrospinal fluid amyloid-β1-42 and plasma apolipoprotein levels

Positional cloning, association analysis and expression studies provide convergent evidence that the cadherin gene FAT contains a bipolar disorder susceptibility allele

Family Based Association Analyses between the Serotonin Transporter Gene Polymorphism (5-HTTLPR) and Neuroticism, Anxiety and Depression

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