Non-coding Genetic Variants in Human Disease

Overview

Journal Hum Mol Genet

Specialties Genetics
Molecular Biology

Date 2015 Jul 9

PMID 26152199

Citations 292

Authors

Feng Zhang

James R Lupski

Affiliations

Soon will be listed here.

Abstract

Genetic variants, including single-nucleotide variants (SNVs) and copy number variants (CNVs), in the non-coding regions of the human genome can play an important role in human traits and complex diseases. Most of the genome-wide association study (GWAS) signals map to non-coding regions and potentially point to non-coding variants, whereas their functional interpretation is challenging. In this review, we discuss the human non-coding variants and their contributions to human diseases in the following four parts. (i) Functional annotations of non-coding SNPs mapped by GWAS: we discuss recent progress revealing some of the molecular mechanisms for GWAS signals affecting gene function. (ii) Technical progress in interpretation of non-coding variants: we briefly describe some of the technologies for functional annotations of non-coding variants, including the methods for genome-wide mapping of chromatin interaction, computational tools for functional predictions and the new genome editing technologies useful for dissecting potential functional consequences of non-coding variants. (iii) Non-coding CNVs in human diseases: we review our emerging understanding the role of non-coding CNVs in human disease. (iv) Compound inheritance of large genomic deletions and non-coding variants: compound inheritance at a locus consisting of coding variants plus non-coding ones is described.

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References

de Kok Y, Vossenaar E, Cremers C, Dahl N, Laporte J, Hu L . Identification of a hot spot for microdeletions in patients with X-linked deafness type 3 (DFN3) 900 kb proximal to the DFN3 gene POU3F4. Hum Mol Genet. 1996; 5(9):1229-35. DOI: 10.1093/hmg/5.9.1229. View

Lacaria M, Spencer C, Gu W, Paylor R, Lupski J . Enriched rearing improves behavioral responses of an animal model for CNV-based autistic-like traits. Hum Mol Genet. 2012; 21(14):3083-96. PMC: 3384379. DOI: 10.1093/hmg/dds124. View

Stadhouders R, Aktuna S, Thongjuea S, Aghajanirefah A, Pourfarzad F, van IJcken W . HBS1L-MYB intergenic variants modulate fetal hemoglobin via long-range MYB enhancers. J Clin Invest. 2014; 124(4):1699-710. PMC: 3973089. DOI: 10.1172/JCI71520. View

Lee J, Madrid R, Sperle K, Ritterson C, Hobson G, Garbern J . Spastic paraplegia type 2 associated with axonal neuropathy and apparent PLP1 position effect. Ann Neurol. 2005; 59(2):398-403. DOI: 10.1002/ana.20732. View

Zhang F, Seeman P, Liu P, Weterman M, Gonzaga-Jauregui C, Towne C . Mechanisms for nonrecurrent genomic rearrangements associated with CMT1A or HNPP: rare CNVs as a cause for missing heritability. Am J Hum Genet. 2010; 86(6):892-903. PMC: 3032071. DOI: 10.1016/j.ajhg.2010.05.001. View

Wieczorek D, Newman W, Wieland T, Berulava T, Kaffe M, Falkenstein D . Compound heterozygosity of low-frequency promoter deletions and rare loss-of-function mutations in TXNL4A causes Burn-McKeown syndrome. Am J Hum Genet. 2014; 95(6):698-707. PMC: 4259969. DOI: 10.1016/j.ajhg.2014.10.014. View

Shalem O, Sanjana N, Zhang F . High-throughput functional genomics using CRISPR-Cas9. Nat Rev Genet. 2015; 16(5):299-311. PMC: 4503232. DOI: 10.1038/nrg3899. View

Gheldof N, Witwicki R, Migliavacca E, Leleu M, Didelot G, Harewood L . Structural variation-associated expression changes are paralleled by chromatin architecture modifications. PLoS One. 2013; 8(11):e79973. PMC: 3827143. DOI: 10.1371/journal.pone.0079973. View

Rao S, Huntley M, Durand N, Stamenova E, Bochkov I, Robinson J . A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell. 2014; 159(7):1665-80. PMC: 5635824. DOI: 10.1016/j.cell.2014.11.021. View

10.

Stenson P, Mort M, Ball E, Howells K, Phillips A, Thomas N . The Human Gene Mutation Database: 2008 update. Genome Med. 2009; 1(1):13. PMC: 2651586. DOI: 10.1186/gm13. View

11.

Ripke S, ODushlaine C, Chambert K, Moran J, Kahler A, Akterin S . Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat Genet. 2013; 45(10):1150-9. PMC: 3827979. DOI: 10.1038/ng.2742. View

12.

Lupski J, Belmont J, Boerwinkle E, Gibbs R . Clan genomics and the complex architecture of human disease. Cell. 2011; 147(1):32-43. PMC: 3656718. DOI: 10.1016/j.cell.2011.09.008. View

13.

Lupski J . Genomic disorders: structural features of the genome can lead to DNA rearrangements and human disease traits. Trends Genet. 1998; 14(10):417-22. DOI: 10.1016/s0168-9525(98)01555-8. View

14.

Edwards S, Beesley J, French J, Dunning A . Beyond GWASs: illuminating the dark road from association to function. Am J Hum Genet. 2013; 93(5):779-97. PMC: 3824120. DOI: 10.1016/j.ajhg.2013.10.012. View

15.

Ahonen T, Saltevo J, Laakso M, Kautiainen H, Kumpusalo E, Vanhala M . Gender differences relating to metabolic syndrome and proinflammation in Finnish subjects with elevated blood pressure. Mediators Inflamm. 2009; 2009:959281. PMC: 2730476. DOI: 10.1155/2009/959281. View

16.

Kraft K, Geuer S, Will A, Chan W, Paliou C, Borschiwer M . Deletions, Inversions, Duplications: Engineering of Structural Variants using CRISPR/Cas in Mice. Cell Rep. 2015; 10(5):833-839. DOI: 10.1016/j.celrep.2015.01.016. View

17.

Abecasis G, Auton A, Brooks L, DePristo M, Durbin R, Handsaker R . An integrated map of genetic variation from 1,092 human genomes. Nature. 2012; 491(7422):56-65. PMC: 3498066. DOI: 10.1038/nature11632. View

18.

Koren A, Handsaker R, Kamitaki N, Karlic R, Ghosh S, Polak P . Genetic variation in human DNA replication timing. Cell. 2014; 159(5):1015-1026. PMC: 4359889. DOI: 10.1016/j.cell.2014.10.025. View

19.

Donnelly C, Zhang P, Pham J, Haeusler A, Heusler A, Mistry N . RNA toxicity from the ALS/FTD C9ORF72 expansion is mitigated by antisense intervention. Neuron. 2013; 80(2):415-28. PMC: 4098943. DOI: 10.1016/j.neuron.2013.10.015. View

20.

Taylor J, Martin H, Lise S, Broxholme J, Cazier J, Rimmer A . Factors influencing success of clinical genome sequencing across a broad spectrum of disorders. Nat Genet. 2015; 47(7):717-726. PMC: 4601524. DOI: 10.1038/ng.3304. View