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Dec 2012, Vol 69, No. 12 >

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Original Article | Dec 2012

Highly Penetrant Alterations of a Critical Region Including BDNF in Human Psychopathology and Obesity

Carl Ernst, PhD; Christian R. Marshall, PhD; Yiping Shen, PhD; Kay Metcalfe, MD; Jill Rosenfeld, PhD; Jennelle C. Hodge, PhD; Alcy Torres, MD; Ian Blumenthal, BSE; Colby Chiang, BA; Vamsee Pillalamarri, MS; Liam Crapper, BSc; Alpha B. Diallo, PhD; Douglas Ruderfer, MSc; Shahrin Pereira, BSc; Pamela Sklar, MD, PhD; Shaun Purcell, PhD; Robert S. Wildin, MD; Anne C. Spencer, MSc; Bradley F. Quade, MD, PhD; David J. Harris, MD; Emanuelle Lemyre, MD; Bai-lin Wu, PhD; Dimitri J. Stavropoulos, PhD; Michael T. Geraghty, MSc; Lisa G. Shaffer, PhD; Cynthia C. Morton, PhD; Stephen W. Scherer, PhD; James F. Gusella, PhD; Michael E. Talkowski, PhD
Arch Gen Psychiatry. 2012;69(12):1238-1246. doi:10.1001/archgenpsychiatry.2012.660.
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Context  Brain-derived neurotrophic factor (BDNF) is suspected of being a causative factor in psychiatric disorders based on case reports or studies involving large structural anomalies.

Objective  To determine the involvement of BDNF in human psychopathology.

Design  Case-control study.

Setting  Microarray-based comparative genomic hybridization data from 7 molecular diagnostic centers including 38 550 affected subjects and 28 705 unaffected subjects.

Patients  Subjects referred to diagnostic screening centers for microarray-based comparative genomic hybridization for physical or cognitive impairment.

Main Outcome Measures  Genomic copy number gains and losses.

Results  We report 5 individuals with psychopathology and genomic deletion of a critical region including BDNF. The defined critical region was never disrupted in control subjects or diagnostic cases without developmental abnormalities.

Conclusion  Hemizygosity of the BDNF region contributes to variable psychiatric phenotypes including anxiety, behavioral, and mood disorders.
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Figure 1. All cases and controls (CTRL) with copy gains (blue) or losses (red) near the BDNF locus. Megabase marks (Mb) represent human genome reference 18 build coordinates. Green shading represents an identified critical region while darker green shading corresponds specifically to the genomic location of BDNF.

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Figure 2. An approximately 2.5-megabase deletion in subject 2, including BDNF. Microarray-based comparative genomic hybridization results demonstrating a deletion on chromosome 11. Gray shading represents the predicted size of the deletion, while individual probes from the array are represented by black, white, or red dots. White probes represent decreased probe intensity from DNA from subject 2, reflecting copy loss. Human genome reference 18 build coordinates are shown on the x-axis.

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Figure 3. Positive correlation of body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) with age in subjects with a BDNF deletion.

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