The role of tandem repeat expansions in brain disorders

Panoyan, Mary Anne; Wendt, Frank R.

doi:10.1042/etls20230022

Cited by 4 publications

(1 citation statement)

References 87 publications

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“…Because of this behavior, TREs may be multi-allelic and offer greater resolution of the genotype–phenotype relationship by linking the length of the TRE to gene expression and trait variation ( 15 – 20 ). Extensive research has connected TRE variation to rare disorders like Huntington’s disease, muscular dystrophies, and some neurological conditions ( 21 ). However, more recent work has demonstrated a large and independent contribution of TRE variation to common complex traits like height, cholesterol concentration, and blood traits ( 16 , 17 , 19 ).…”

Section: Introductionmentioning

confidence: 99%

Association between suicidal ideation and tandem repeats in contactins

Parikh,

Quintero Reis,

Wendt

2024

Front. Psychiatry

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BackgroundDeath by suicide is one of the leading causes of death among adolescents. Genome-wide association studies (GWAS) have identified loci that associate with suicidal ideation and related behaviours. One such group of loci are the six contactin genes (CNTN1-6) that are critical to neurodevelopment through regulating neurite structure. Because single nucleotide polymorphisms (SNPs) detected by GWAS often map to non-coding intergenic regions, we investigated whether repetitive variants in CNTNs associated with suicidality in a young cohort aged 8 to 21. Understanding the genetic liability of suicidal thought and behavior in this age group will promote early intervention and treatment.MethodsGenotypic and phenotypic data were obtained from the Philadelphia Neurodevelopment Cohort (PNC). Across six CNTNs, 232 short tandem repeats (STRs) were analyzed in up to 4,595 individuals of European ancestry who expressed current, previous, or no suicidal ideation. STRs were imputed into SNP arrays using a phased SNP-STR haplotype reference panel from the 1000 Genomes Project. We tested several additive and interactive models of locus-level burden (i.e., sum of STR alleles) with respect to suicidal ideation. Additive models included sex, birth year, developmental stage (“DevStage”), and the first 10 principal components of ancestry as covariates; interactive models assessed the effect of STR-by-DevStage considering all other covariates.ResultsCNTN1-[T]N interacted with DevStage to increase risk for current suicidal ideation (CNTN1-[T]N-by-DevStage; p = 0.00035). Compared to the youngest age group, the middle (OR = 1.80, p = 0.0514) and oldest (OR = 3.82, p = 0.0002) participant groups had significantly higher odds of suicidal ideation as their STR length expanded; this result was independent of polygenic scores for suicidal ideation.DiscussionThese findings highlight diversity in the genetic effects (i.e., SNP and STR) acting on suicidal thoughts and behavior and advance our understanding of suicidal ideation across childhood and adolescence.

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Section: Introductionmentioning

confidence: 99%

Association between suicidal ideation and tandem repeats in contactins

Parikh,

Quintero Reis,

Wendt

2024

Front. Psychiatry

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Expanding horizons of tandem repeats in biology and medicine: Why ‘genomic dark matter’ matters

Hannan

2023

Emerging Topics in Life Sciences

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Approximately half of the human genome includes repetitive sequences, and these DNA sequences (as well as their transcribed repetitive RNA and translated amino-acid repeat sequences) are known as the repeatome. Within this repeatome there are a couple of million tandem repeats, dispersed throughout the genome. These tandem repeats have been estimated to constitute ∼8% of the entire human genome. These tandem repeats can be located throughout exons, introns and intergenic regions, thus potentially affecting the structure and function of tandemly repetitive DNA, RNA and protein sequences. Over more than three decades, more than 60 monogenic human disorders have been found to be caused by tandem-repeat mutations. These monogenic tandem-repeat disorders include Huntington's disease, a variety of ataxias, amyotrophic lateral sclerosis and frontotemporal dementia, as well as many other neurodegenerative diseases. Furthermore, tandem-repeat disorders can include fragile X syndrome, related fragile X disorders, as well as other neurological and psychiatric disorders. However, these monogenic tandem-repeat disorders, which were discovered via their dominant or recessive modes of inheritance, may represent the ‘tip of the iceberg’ with respect to tandem-repeat contributions to human disorders. A previous proposal that tandem repeats may contribute to the ‘missing heritability’ of various common polygenic human disorders has recently been supported by a variety of new evidence. This includes genome-wide studies that associate tandem-repeat mutations with autism, schizophrenia, Parkinson's disease and various types of cancers. In this article, I will discuss how tandem-repeat mutations and polymorphisms could contribute to a wide range of common disorders, along with some of the many major challenges of tandem-repeat biology and medicine. Finally, I will discuss the potential of tandem repeats to be therapeutically targeted, so as to prevent and treat an expanding range of human disorders.

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Exome-wide tandem repeats confer large effects on subcortical volumes in UK Biobank participants

Panoyan,

Shi,

Abbatangelo

et al. 2023

Preprint

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The human subcortex is involved in memory and cognition. Structural and functional changes in subcortical regions is implicated in psychiatric conditions. We performed an association study of subcortical volumes using 15,941 tandem repeats (TRs) derived from whole exome sequencing (WES) data in 16,527 unrelated European ancestry participants. We identified 17 loci, most of which were associated with accumbens volume, and nine of which had fine-mapping probability supporting their causal effect on subcortical volume independent of surrounding variation. The most significant association involvedNTN1-[GCGG]Nand increased accumbens volume (β=5.93, P=8.16x10-9). Three exonic TRs had large effects on thalamus volume (LAT2-[CATC]Nβ=-949, P=3.84x10-6andSLC39A4-[CAG]Nβ=-1599, P=2.42x10-8) and pallidum volume (MCM2-[AGG]Nβ=-404.9, P=147x10-7). These genetic effects were consistent measurements of per-repeat expansion/contraction effects on organism fitness. With 3-dimensional modeling, we reinforced these effects to show that the expanded and contractedLAT2-[CATC]Nrepeat causes a frameshift mutation that prevents appropriate protein folding. These TRs also exhibited independent effects on several psychiatric symptoms, includingLAT2-[CATC]Nand the tiredness/low energy symptom of depression (β=0.340, P=0.003). These findings link genetic variation to tractable biology in the brain and relevant psychiatric symptoms. We also chart one pathway for TR prioritization in future complex trait genetic studies.

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The role of tandem repeat expansions in brain disorders

Cited by 4 publications

References 87 publications

Association between suicidal ideation and tandem repeats in contactins

Association between suicidal ideation and tandem repeats in contactins

Expanding horizons of tandem repeats in biology and medicine: Why ‘genomic dark matter’ matters

Exome-wide tandem repeats confer large effects on subcortical volumes in UK Biobank participants

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