Dose Response of the 16p11.2 Distal Copy Number Variant on Intracranial Volume and Basal Ganglia

Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = -0.71 to -1.37; P < 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (β = -0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P = 0.0032, 8.9 × 10, 1.7 × 10, 3.5 × 10 and 1.0 × 10, respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes.

Citing Articles

Copy Number Variations of the Gene and Their Associations with Growth Traits in Three Chinese Sheep Breeds.

Cao X, Liu Y, Cheng J, Ling C, Huang J, Sun W Genes (Basel). 2025; 16(2).

PMID: 40004547 PMC: 11855597. DOI: 10.3390/genes16020218.

[Long-term courses of bipolar disorders].

Czempiel T, Mikolas P, Bauer M, Vogel S, Ritter P Nervenarzt. 2024; 96(1):15-22.

PMID: 39709326 PMC: 11772376. DOI: 10.1007/s00115-024-01791-6.

Genomic analysis of intracranial and subcortical brain volumes yields polygenic scores accounting for variation across ancestries.

Garcia-Marin L, Campos A, Diaz-Torres S, Rabinowitz J, Ceja Z, Mitchell B Nat Genet. 2024; 56(11):2333-2344.

PMID: 39433889 DOI: 10.1038/s41588-024-01951-z.

Ras, RhoA, and vascular pharmacology in neurodevelopment and aging.

Nussinov R, Jang H, Cheng F Neurochem Int. 2024; 181:105883.

PMID: 39427854 PMC: 11614691. DOI: 10.1016/j.neuint.2024.105883.

Genomic analysis of intracranial and subcortical brain volumes yields polygenic scores accounting for variation across ancestries.

Garcia-Marin L, Campos A, Diaz-Torres S, Rabinowitz J, Ceja Z, Mitchell B medRxiv. 2024; .

PMID: 39371125 PMC: 11451674. DOI: 10.1101/2024.08.13.24311922.

References

Sampson M, Coughlin 2nd C, Kaplan P, Conlin L, Meyers K, Zackai E . Evidence for a recurrent microdeletion at chromosome 16p11.2 associated with congenital anomalies of the kidney and urinary tract (CAKUT) and Hirschsprung disease. Am J Med Genet A. 2010; 152A(10):2618-22. DOI: 10.1002/ajmg.a.33628. View

Loviglio M, Leleu M, Mannik K, Passeggeri M, Giannuzzi G, van der Werf I . Chromosomal contacts connect loci associated with autism, BMI and head circumference phenotypes. Mol Psychiatry. 2016; 22(6):836-849. PMC: 5508252. DOI: 10.1038/mp.2016.84. View

Reinthaler E, Lal D, Lebon S, Hildebrand M, Dahl H, Regan B . 16p11.2 600 kb Duplications confer risk for typical and atypical Rolandic epilepsy. Hum Mol Genet. 2014; 23(22):6069-80. DOI: 10.1093/hmg/ddu306. View

Martin-Brevet S, Rodriguez-Herreros B, Nielsen J, Moreau C, Modenato C, Maillard A . Quantifying the Effects of 16p11.2 Copy Number Variants on Brain Structure: A Multisite Genetic-First Study. Biol Psychiatry. 2018; 84(4):253-264. DOI: 10.1016/j.biopsych.2018.02.1176. View

Bochukova E, Huang N, Keogh J, Henning E, Purmann C, Blaszczyk K . Large, rare chromosomal deletions associated with severe early-onset obesity. Nature. 2009; 463(7281):666-70. PMC: 3108883. DOI: 10.1038/nature08689. View

Jacquemont S, Reymond A, Zufferey F, Harewood L, Walters R, Kutalik Z . Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus. Nature. 2011; 478(7367):97-102. PMC: 3637175. DOI: 10.1038/nature10406. View

Wang K, Li M, Hadley D, Liu R, Glessner J, Grant S . PennCNV: an integrated hidden Markov model designed for high-resolution copy number variation detection in whole-genome SNP genotyping data. Genome Res. 2007; 17(11):1665-74. PMC: 2045149. DOI: 10.1101/gr.6861907. View

Barber J, Hall V, Maloney V, Huang S, Roberts A, Brady A . 16p11.2-p12.2 duplication syndrome; a genomic condition differentiated from euchromatic variation of 16p11.2. Eur J Hum Genet. 2012; 21(2):182-9. PMC: 3548261. DOI: 10.1038/ejhg.2012.144. View

Ballif B, Hornor S, Jenkins E, Madan-Khetarpal S, Surti U, Jackson K . Discovery of a previously unrecognized microdeletion syndrome of 16p11.2-p12.2. Nat Genet. 2007; 39(9):1071-3. DOI: 10.1038/ng2107. View

10.

Shen Y, Chen X, Wang L, Guo J, Shen J, An Y . Intra-family phenotypic heterogeneity of 16p11.2 deletion carriers in a three-generation Chinese family. Am J Med Genet B Neuropsychiatr Genet. 2011; 156(2):225-32. DOI: 10.1002/ajmg.b.31147. View

11.

Insel T . Rethinking schizophrenia. Nature. 2010; 468(7321):187-93. DOI: 10.1038/nature09552. View

12.

Marshall C, Howrigan D, Merico D, Thiruvahindrapuram B, Wu W, Greer D . Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects. Nat Genet. 2016; 49(1):27-35. PMC: 5737772. DOI: 10.1038/ng.3725. View

13.

Tabet A, Pilorge M, Delorme R, Amsellem F, Pinard J, Leboyer M . Autism multiplex family with 16p11.2p12.2 microduplication syndrome in monozygotic twins and distal 16p11.2 deletion in their brother. Eur J Hum Genet. 2012; 20(5):540-6. PMC: 3330222. DOI: 10.1038/ejhg.2011.244. View

14.

Maillard A, Ruef A, Pizzagalli F, Migliavacca E, Hippolyte L, Adaszewski S . The 16p11.2 locus modulates brain structures common to autism, schizophrenia and obesity. Mol Psychiatry. 2014; 20(1):140-7. PMC: 4320286. DOI: 10.1038/mp.2014.145. View

15.

Sanders S, Ercan-Sencicek A, Hus V, Luo R, Murtha M, Moreno-De-Luca D . Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron. 2011; 70(5):863-85. PMC: 3939065. DOI: 10.1016/j.neuron.2011.05.002. View

16.

Qureshi A, Mueller S, Snyder A, Mukherjee P, Berman J, Roberts T . Opposing brain differences in 16p11.2 deletion and duplication carriers. J Neurosci. 2014; 34(34):11199-211. PMC: 4138332. DOI: 10.1523/JNEUROSCI.1366-14.2014. View

17.

Bijlsma E, Gijsbers A, Schuurs-Hoeijmakers J, van Haeringen A, Fransen van de Putte D, Anderlid B . Extending the phenotype of recurrent rearrangements of 16p11.2: deletions in mentally retarded patients without autism and in normal individuals. Eur J Med Genet. 2009; 52(2-3):77-87. DOI: 10.1016/j.ejmg.2009.03.006. View

18.

Loviglio M, Arbogast T, Jonch A, Collins S, Popadin K, Bonnet C . The Immune Signaling Adaptor LAT Contributes to the Neuroanatomical Phenotype of 16p11.2 BP2-BP3 CNVs. Am J Hum Genet. 2017; 101(4):564-577. PMC: 5630231. DOI: 10.1016/j.ajhg.2017.08.016. View

19.

Battaglia A, Novelli A, Bernardini L, Igliozzi R, Parrini B . Further characterization of the new microdeletion syndrome of 16p11.2-p12.2. Am J Med Genet A. 2009; 149A(6):1200-4. DOI: 10.1002/ajmg.a.32847. View

20.

Mace A, Tuke M, Deelen P, Kristiansson K, Mattsson H, Noukas M . CNV-association meta-analysis in 191,161 European adults reveals new loci associated with anthropometric traits. Nat Commun. 2017; 8(1):744. PMC: 5622064. DOI: 10.1038/s41467-017-00556-x. View