A Genome Scan for Modifiers of Age at Onset in Huntington Disease: The HD MAPS Study

Li, Jian Liang; Hayden, Michael R.; Almqvist, E; Brinkman, Ryan R.; Dürr, Alexandra; Dodé, Catherine; Morrison, Patrick J.; Suchowersky, Oksana; Ross, Christopher A.; Margolis, Russell L.; Rosenblatt, Adam; Gómez‐Tortosa, Estrella; Cabrero, David Mayo; Novelletto, Andrea; Frontali, Marina; Nance, Martha; Trent, Ronald J.; McCusker, Elizabeth; Jones, Randi; Paulsen, Jane S.; Harrison, Madeline; Zanko, Andrea; Abramson, Ruth K.; Russ, Ana L.; Knowlton, Beth; Djoussé, Luc; Mysore, Jayalakshmi Srinidhi; Tariot, Suzanne; Gusella, Michael F.; Wheeler, Vanessa C.; Atwood, Larry D.; Cupples, L. Adrienne; Saint-Hilaire, Marie H.; Jang, Jinhee; Hersch, Steven M.; Koroshetz, Walter J.; Gusella, James F.; MacDonald, Marcy E.; Myers, Richard H.

doi:10.1086/378133

Cited by 141 publications

(102 citation statements)

References 14 publications

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“…We use this probability rather than estimated years to diagnosis because preliminary analyses of relationships with striatal volumes and other clinical variables suggests that more linear and thus more easily modeled relationships are likely using the probability scale (Paulsen et al, under review). The difference from parent onset age was calculated by subtracting the participant's current age from the parent's age at disease onset; this number serves as an indirect control for possible additional environmental or minor genetic influences on the age of HD onset (Djousse et al, 2003;Li et al, 2003). Thus, we include parent onset age as a possible source of variance in HVLT-R performance independent of CAG length.…”

Section: Participant Characterizationmentioning

confidence: 99%

Verbal episodic memory declines prior to diagnosis in Huntington's disease

et al. 2007

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Section: Participant Characterizationmentioning

confidence: 99%

Verbal episodic memory declines prior to diagnosis in Huntington's disease

et al. 2007

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“…5,7,10 Several studies have attempted to make use of genome-wide analyses in order to identify genetic modifiers and better understand HD aetiology and pathogenesis. [11][12][13] A number of processes were implicated in early disease pathogenesis; however, specific genetic modifiers are still under investigation. 14 Support for the hypothesis that genetic background may modulate the CAG mutation rate has recently been shown at a population level.…”

Section: Introductionmentioning

confidence: 99%

Huntington disease in the South African population occurs on diverse and ethnically distinct genetic haplotypes

et al. 2013

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Huntington disease (HD) is a neurodegenerative disorder resulting from the expansion of a CAG trinucleotide repeat in the huntingtin (HTT) gene. Worldwide prevalence varies geographically with the highest figures reported in populations of European ancestry. HD in South Africa has been reported in Caucasian, black and mixed subpopulations, with similar estimated prevalence in the Caucasian and mixed groups and a lower estimate in the black subpopulation. Recent studies have associated specific HTT haplotypes with HD in distinct populations. Expanded HD alleles in Europe occur predominantly on haplogroup A (specifically high-risk variants A1/A2), whereas in East Asian populations, HD alleles are associated with haplogroup C. Whether specific HTT haplotypes associate with HD in black Africans and how these compare with haplotypes found in European and East Asian populations remains unknown. The current study genotyped the HTT region in unaffected individuals and HD patients from each of the South African subpopulations, and haplotypes were constructed. CAG repeat sizes were determined and phased to haplotype. Results indicate that HD alleles from Caucasian and mixed patients are predominantly associated with haplogroup A, signifying a similar European origin for HD. However, in black patients, HD occurs predominantly on haplogroup B, suggesting several distinct origins of the mutation in South Africa. The absence of high-risk variants (A1/A2) in the black subpopulation may also explain the reported low prevalence of HD. Identification of haplotypes associated with HD-expanded alleles is particularly relevant to the development of population-specific therapeutic targets for selective suppression of the expanded HTT transcript.

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“…Suggestive evidence for linkage distal to F-4 was also demonstrated for a modifier gene in Huntington's disease. 54 The fifth focus (F-5) is at 162 Mb with the strongest evidence for linkage on 6q 29 in an SCZ pedigree. Although there are no other supporting linkage studies, altered levels have been shown in the hippocampus of schizophrenics for two proteins encoded by genes in this location (TCP1 and MnSOD).…”

Section: Discussionmentioning

confidence: 99%

“…53 This is the marker that gave weak positive results in a linkage study of psychosis in BPD. 46 Li et al 54 found suggestive evidence for a modifier gene for age of onset in Huntington's disease at 6q24 with an LOD score of 2.28 at 148 Mb. Suggestive linkage for phonological coding dyslexia was found for several markers at 6q, 55 spanning the interval between D6S965 and D6S251 (70-82 Mb).…”

Section: Findings In Other Neuropsychiatric Disordersmentioning

confidence: 99%

Excitement and confusion on chromosome 6q: the challenges of neuropsychiatric genetics in microcosm

Kohn¹,

Lerer²

2005

Mol Psychiatry

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The search for genes that are implicated in the pathogenesis of schizophrenia (SCZ), bipolar disorder (BPD) and other complex neuropsychiatric phenotypes has yielded a plethora of positive findings, but has also engendered a substantial degree of confusion. Exciting findings include positive linkage results in a number of chromosomal regions and the identification of several genes that have been associated with SCZ and to a lesser extent with BPD. Confusing aspects include the difference between studies in localization of linkage peaks in the same chromosomal regions, raising the possibility that these regions may harbor more than one gene, the fact that positive linkage findings as well as associated genes appear in several cases to be shared by more than one disorder, and the failure to identify thus far the precise pathogenic variants in associated genes. Recent findings of linkage and association studies on chromosome 6q illustrate the current status of neuropsychiatric genetics in intriguing microcosm. Positive findings from linkage and association studies are reviewed in order to identify approaches that may help to settle apparent contradictions and allow an interpretation of the results that may prove useful in application to findings from other chromosomal regions. Not only SCZ and BPD but also other psychiatric and neurological phenotypes are considered. Taking a topographic approach, we identify five foci of positive findings on chromosome 6q and suggest that each may harbor gene(s) that confer susceptibility to SCZ or BPD or may modify their onset or clinical course. We further suggest that in searching for these genes the possibility that they may be implicated in more than one disorder should be taken into account. We also discuss the potential contribution of rare genetic variants identified in homogeneous, isolated populations to the subsequent identification of common variants in the same gene that contribute to disease susceptibility in outbred populations. Keywords: schizophrenia; bipolar disorder; chromosome 6q; molecular genetics; linkageThe last three decades have seen considerable advances in the field of psychiatric genetics. First, family twin and adoption studies conclusively established that genes play a major role in the etiology of many psychiatric disorders. Then, an increasing number of groups embarked on linkage studies aiming at localizing these genes. With ever improving technology, whole genome scans became the standard vehicle for these endeavors. Studies became more and more sophisticated, involving larger samples of carefully characterized affected individuals, using denser maps of markers and employing increasingly powerful statistical tools. Over the years, linkage studies have repeatedly implicated several chromosomal regions as linked to major psychiatric disorders, particularly schizophrenia (SCZ) and bipolar disorder (BPD) (for reviews, see Riley and McGuffin, 1 Berrettini,2 Kohn and Lerer 3 and Mathews and Reus 4 ). Recent meta-analyses of linkage studies have establi...

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A Genome Scan for Modifiers of Age at Onset in Huntington Disease: The HD MAPS Study

Cited by 141 publications

References 14 publications

Verbal episodic memory declines prior to diagnosis in Huntington's disease

Verbal episodic memory declines prior to diagnosis in Huntington's disease

Huntington disease in the South African population occurs on diverse and ethnically distinct genetic haplotypes

Excitement and confusion on chromosome 6q: the challenges of neuropsychiatric genetics in microcosm

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