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Las variantes de codificación raras en el gen fosfolipasa D3 confieren riesgo de enfermedad de Alzheimer

Carlos Cruchaga^1,2, Celeste M Karch^1,2, Sheng Chih Jin¹

¹Department of Psychiatry, Washington University, St. Louis, MO, USA.

|December 17, 2013

Resumen

Una variante rara en el gen PLD3 aumenta significativamente el riesgo de enfermedad de Alzheimer de aparición tardía (LOAD). Este hallazgo pone de relieve el papel de PLD3 en la patología de la enfermedad de Alzheimer y el procesamiento de APP.

Área de la Ciencia:

Genética La genética.
La neurociencia es la neurociencia.
Biología Molecular Biología Molecular

Sus antecedentes:

Los estudios de asociación de todo el genoma (GWAS) han identificado variantes comunes asociadas con la enfermedad de Alzheimer de aparición tardía (LOAD), pero estas típicamente tienen efectos pequeños.
Se predice que las variantes de codificación de baja frecuencia, a menudo pasadas por alto por GWAS, alberguen variantes funcionales con impactos potencialmente mayores en el riesgo de enfermedad.

Objetivo del estudio:

Para identificar variantes de codificación de baja frecuencia con efectos significativos en el riesgo de LOAD.
Para investigar el papel del gen de la fosfolipasa D3 (PLD3) en la patogénesis de la enfermedad de Alzheimer.

Principales métodos:

Se realizó la secuenciación del exoma entero (WES) en 14 familias grandes de LOAD.
Las variantes candidatas se sometieron a análisis de seguimiento en múltiples conjuntos de datos de casos y controles de LOAD grandes.
Se realizaron análisis de carga genética y estudios funcionales (expresión génica, niveles de proteínas).

Principales resultados:

Una variante rara de PLD3 (Val232Met) se segregó con la enfermedad en las familias y duplicó el riesgo de LOAD en más de 11,000 individuos.
Se descubrió que múltiples variantes de PLD3 aumentan el riesgo de enfermedad de Alzheimer tanto en las poblaciones europeas como en las afroamericanas.
La expresión de PLD3 se reduce en los cerebros de la enfermedad de Alzheimer, y el gen influye en el procesamiento de la proteína precursora amiloide (APP), afectando los niveles de Aβ42 y Aβ40.

Conclusiones:

Las variantes de codificación en PLD3 confieren un riesgo duplicado de LOAD.
PLD3 juega un papel crucial en el procesamiento de APP y está implicado en la enfermedad de Alzheimer.
Las familias densamente afectadas son valiosas para identificar variantes genéticas raras y de alto impacto para enfermedades complejas.

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