An Assessment of Gene-By-Gene Interactions As a Tool to Unfold Missing Heritability In

An assessment of gene-by-gene interactions as a tool to unfold missing heritability in dyslexia

Mascheretti S1, Bureau A2,3, Trezzi V1, Giorda R4, Marino C1,2,5

1Child Psychopathology Unit, Scientiﬁc Institute, IRCCS Eugenio Medea, Bosisio Parini, Italy

2Centre de recherche de l’institut universitaire en santé mentale de Québec, Quebec City, Canada

3Department of Social and Preventive Medicine, Faculty of Medicine, Laval University, Quebec City, Canada

4Molecular Biology Lab, Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Italy

5Department of Psychiatry and Neuroscience, Faculty of Medicine, Laval University, Quebec City, Canada

Journal name: Human Genetics

Corresponding author:

Sara Mascheretti, Ph.D.

Child Psychopathology Unit, Scientiﬁc Institute, IRCCS Eugenio Medea

Bosisio Parini (Lecco), 23842, Italy

Phone: +39 031 877924

Fax: +39 031 877499

email:

Supplementary Material 3_Mascheretti

Supplementary Material 3.Significant pairwise GxG effects before Bonferroni correction between the DYX1C1, DCDC2, ROBO1, KIAA0319and GRIN2B markers on neuropsychological composite.

Reading composite
A: DYX1C1- 3G/A / A: DYX1C1 - 1259C/G / A: DCDC2-rs793862A/G / A: TTRAP-rs2143340A/G
B: ROBO1-rs9853895C/T / B: GRIN2B-rs2268119A/T / B: DCDC2-rs793862A/G / B: GRIN2B-rs11609779C/T
β / St. error / p / β / St. error / p / β / St. error / p / β / St. error / p / β / St. error / p
Intercept / -2.031 / 0.150 / < 0.001 / -2.092 / 0.129 / <0.001 / -1.841 / 0.140 / <0.001 / -1.909 / 0.153 / <0.001 / -2.157 / 0.135 / <0.001
a / 0.608 / 0.309 / 0.051 / 0.391 / 0.273 / 0.153 / -0.572 / 0.261 / 0.030 / -0.333 / 0.152 / 0.030 / 0.389 / 0.187 / 0.039
b / 0.078 / 0.133 / 0.559 / 0.072 / 0.157 / 0.647 / -0.243 / 0.134 / 0.070 / -0.112 / 0.203 / 0.581 / 0.342 / 0.168 / 0.043
Gender / 0.356 / 0.170 / 0.037 / 0.395 / 0.169 / 0.021 / 0.430 / 0.166 / 0.010 / 0.405 / 0.164 / 0.015 / 0.373 / 0.168 / 0.028
ig / -0.796 / 0.321 / 0.017* / -0.846 / 0.397 / 0.035* / 0.637 / 0.302 / 0.037* / 0.468 / 0.209 / 0.027* / -0.790 / 0.297 / 0.009*

a and b are the main effect estimates for the numbers of rare alleles of marker A and marker B, respectively; ig represents an estimate of GxG effect in as much as it indicates the change in the allelic variant association of one marker with the phenotype across the different numbers of rare alleles of the other marker.

Gender refers to female.

* Empirical p-value computed from 500.000 permutations.

Supplementary Material 3_Mascheretti1

Supplementary Material 3.Significant pairwise GxG effects before Bonferroni correction between the DYX1C1, DCDC2, ROBO1, KIAA0319and GRIN2B markers on neuropsychological composite.

Spelling composite
A: DYX1C1-1249G/T / A: ROBO1-rs333491A/G / A: KIAA0319-rs4504469C/T / A: KIAA0319-rs2038137G/T / A: ROBO1-rs333491A/G
B: GRIN2B-rs1012586G/C / B: GRIN2B-rs5796555-/A
β / St. error / p / β / St. error / p / β / St. error / p / β / St. error / p / β / St. error / p
Intercept / -2.253 / 0.235 / <0.001 / -1.919 / 0.322 / <0.001 / -2.651 / 0.270 / <0.001 / -2.701 / 0.256 / <0.001 / -2.051 / 0.301 / <0.001
a / -0.719 / 0.436 / 0.101 / -0.260 / 0.263 / 0.324 / 0.418 / 0.256 / 0.104 / 0.579 / 0.256 / 0.025 / -0.166 / 0.246 / 0.500
b / -0.404 / 0.227 / 0.077 / -0.978 / 0.348 / 0.005 / 0.242 / 0.308 / 0.434 / 0.156 / 0.292 / 0.595 / -0.937 / 0.360 / 0.010
Gender / 0.983 / 0.267 / <0.001 / 0.838 / 0.268 / 0.002 / 0.906 / 0.274 / 0.001 / 0.972 / 0.268 / <0.001 / 0.879 / 0.268 / 0.001
ig / 1.106 / 0.500 / 0.028* / 0.670 / 0.299 / 0.026* / -0.707 / 0.317 / 0.027* / -0.683 / 0.325 / 0.036* / 0.604 / 0.303 / 0.046*

a and b are the main effect estimates for the numbers of rare alleles of marker A and marker B, respectively; ig represents an estimate of GxG effect in as much as it

indicates the change in the allelic variant association of one marker with the phenotype across the different numbers of rare alleles of the other marker.

Gender refers to female.

* Empirical p-value computed from 500.000 permutations.

Supplementary Material 3_Mascheretti1

Supplementary Material 3.Significant pairwise GxG effects before Bonferroni correction between the DYX1C1, DCDC2,

ROBO1, KIAA0319and GRIN2B markers on neuropsychological composite.

Spelling composite
A: DYX1C1-3G/A / A: KIAA0319-rs9461045C/T / A: TTRAP-rs2143340A/G
B: DCDC2-rs793862A/G / B: ROBO1-rs9853895C/T / B: ROBO1-rs7644521C/T
β / β / St. error / p / β / St. error / p / St. error / p
Intercept / -2.713 / 0.227 / <0.001 / -2.421 / 0.273 / <0.001 / -2.372 / 0.214 / <0.001
a / 1.177 / 0.491 / 0.017 / 0.325 / 0.332 / 0.328 / -0.308 / 0.290 / 0.289
b / 0.205 / 0.215 / 0.342 / 0.207 / 0.247 / 0.404 / 0.555 / 0.306 / 0.071
Gender / 0.998 / 0.265 / <0.001 / 0.889 / 0.247 / 0.001 / 0.936 / 0.274 / 0.001
ig / -1.268 / 0.551 / 0.023* / -0.794 / 0.313 / 0.012* / -1.170 / 0.514 / 0.024*

a and b are the main effect estimates for the numbers of rare alleles of marker A and marker B, respectively; ig represents an

estimate of GxG effect in as much as it indicates the change in the allelic variant association of one marker with the phenotype

across the different numbers of rare alleles of the other marker.

Gender refers to female.

* Empirical p-value computed from 500.000 permutations.

Supplementary Material 3.Significant pairwise GxG effects before Bonferroni correction between the DYX1C1, DCDC2, ROBO1, KIAA0319 and GRIN2B

markers on neuropsychological composite.

Memory Letters composite
A: DCDC2-BV677278 / A: ROBO1-rs333491A/G / A: DYX1C1 - 1259C/G / A: DCDC2-rs793862A/G
B: KIAA0319-rs2038137G/T / B: GRIN2B-rs2268119A/T / B: GRIN2B-rs2192973C/T / B: KIAA0319-rs4504469C/T
β / St. error / p / β / St. error / p / β / St. error / p / β / St. error / p
Intercept / -0.564 / 0.073 / <0.001 / -0.708 / 0.098 / <0.001 / -0.714 / 0.075 / <0.001 / -0.743 / 0.103 / <0.001
a / -0.517 / 0.171 / 0.003 / -0.032 / 0.078 / 0.681 / 0.223 / 0.131 / 0.091 / 0.122 / 0.107 / 0.259
b / -0.184 / 0.068 / 0.008 / -0.239 / 0.147 / 0.109 / -0.003 / 0.086 / 0.969 / 0.095 / 0.091 / 0.300
Gender / 0.207 / 0.090 / 0.024 / 0.102 / 0.092 / 0.269 / 0.127 / 0.090 / 0.163 / 0.145 / 0.093 / 0.122
ig / 0.556 / 0.192 / 0.007* / 0.375 / 0.128 / 0.004* / -0.423 / 0.199 / 0.036* / -0.236 / 0.101 / 0.021*

a and b are the main effect estimates for the numbers of rare alleles of marker A and marker B, respectively; ig represents an estimate of GxG effect in as much as it

indicates the change in the allelic variant association of one marker with the phenotype across the different numbers of rare alleles of the other marker.

Gender refers to female.

* Empirical p-value computed from 500.000 permutations.

Supplementary Material 3_Mascheretti1

Supplementary Material 3.Significant pairwise GxG effects before Bonferroni correction between the DYX1C1, DCDC2, ROBO1,

KIAA0319and GRIN2B markers on neuropsychological composite

Memory Letters composite
A: DCDC2-rs793862A/G / A: KIAA0319-rs2038137G/T / A: ROBO1-rs333491A/G
B: GRIN2B-rs11609779C/T / B: GRIN2B-rs5796555-/A / B: GRIN2B-rs1012586G/C
β / St. error / p / β / St. error / p / β / St. error / p / β / St. error / p
Intercept / -0.526 / 0.086 / <0.001 / -0.561 / 0.083 / <0.001 / -0.661 / 0.102 / <0.001 / -0.673 / 0.104 / <0.001
a / -0.187 / 0.085 / 0.029 / -0.200 / 0.078 / 0.012 / -0.026 / 0.083 / 0.754 / -0.022 / 0.085 / 0.800
b / -0.241 / 0.111 / 0.032 / -0.259 / 0.126 / 0.042 / -0.255 / 0.125 / 0.043 / -0.216 / 0.118 / 0.071
Gender / 0.073 / 0.090 / 0.421 / 0.149 / 0.093 / 0.114 / 0.093 / 0.092 / 0.317 / 0.102 / 0.092 / 0.270
ig / 0.246 / 0.109 / 0.027* / 0.300 / 0.125 / 0.022* / 0.246 / 0.103 / 0.019* / 0.215 / 0.101 / 0.034*

a and b are the main effect estimates for the numbers of rare alleles of marker A and marker B, respectively; ig represents an estimate of GxG

effect in as much as it indicates the change in the allelic variant association of one marker with the phenotype across the different numbers of

rare alleles of the other marker.

Gender refers to female.

* Empirical p-value computed from 500.000 permutations.

Supplementary Material 3_Mascheretti1

Supplementary Material 3.Significant pairwise GxG effects before Bonferroni correction between the DYX1C1, DCDC2, ROBO1, KIAA0319and GRIN2B markers on neuropsychological composite.

Memory Digits composite
A: DYX1C1-3G/A / A: DYX1C1 - 1259C/G
B: DCDC2-rs793862A/G / B: GRIN2B-rs2268119A/T / B: GRIN2B-rs1012586G/C / B: KIAA0319-rs9461045C/T / B: GRIN2B-rs5796555-/A / B: GRIN2B-rs2192973C/T
β / St. error / p / β / St. error / p / β / St. error / p / β / St. error / p / β / St. error / p / β / St. error / p
Intercept / -0.329 / 0.087 / <0.001 / -0.386 / 0.082 / <0.001 / -0.280 / 0.086 / 0.001 / -0.352 / 0.082 / <0.001 / -0.293 / 0.083 / 0.001 / -0.367 / 0.085 / <0.001
a / 0.442 / 0.178 / 0.014 / 0.315 / 0.155 / 0.043 / 0.333 / 0.164 / 0.044 / -0.024 / 0.139 / 0.863 / 0.240 / 0.157 / 0.127 / 0.213 / 0.145 / 0.142
b / 0.014 / 0.079 / 0.861 / 0.101 / 0.095 / 0.290 / -0.038 / 0.081 / 0.637 / -0.049 / 0.094 / 0.601 / -0.007 / 0.083 / 0.934 / 0.059 / 0.095 / 0.537
Gender / 0.003 / 0.092 / 0.971 / -0.005 / 0.092 / 0.958 / 0.039 / 0.093 / 0.672 / -0.043 / 0.095 / 0.653 / 0.011 / 0.093 / 0.910 / -0.006 / 0.093 / 0.947
ig / -0.596 / 0.204 / 0.004* / -0.616 / 0.215 / 0.004* / -0.537 / 0.192 / 0.005* / 0.373 / 0.179 / 0.039* / -0.457 / 0.204 / 0.025* / -0.491 / 0.213 / 0.022*

Gender refers to female.

* Empirical p-value computed from 500.000 permutations.

Supplementary Material 3_Mascheretti1

Supplementary Material 3.Significant pairwise GxG effects before Bonferroni correction between the DYX1C1, DCDC2, ROBO1, KIAA0319and GRIN2B markers on neuropsychological composite.

Memory Digits composite
A: DCDC2-BV677278 / A: KIAA0319-rs4504469C/T / A: KIAA0319-rs2038137G/T / A: TTRAP-rs2143340A/G
B: ROBO1-rs7644521C/T / B: GRIN2B-rs11609779C/T / B: GRIN2B-rs2216128T/C
β / St. error / p / β / St. error / p / β / St. error / p / β / St. error / p / β / St. error / p
Intercept / -0.352 / 0.073 / <0.001 / -0.492 / 0.093 / <0.001 / -0.454 / 0.088 / <0.001 / -0.250 / 0.090 / 0.006 / -0.404 / 0.084 / <0.001
a / -0.293 / 0.155 / 0.061 / 0.111 / 0.082 / 0.176 / 0.063 / 0.081 / 0.437 / -0.216 / 0.084 / 0.011 / 0.146 / 0.113 / 0.199
b / -0.113 / 0.098 / 0.249 / 0.213 / 0.133 / 0.111 / 0.217 / 0.127 / 0.088 / -0.211 / 0.126 / 0.095 / 0.054 / 0.106 / 0.613
Gender / -0.016 / 0.090 / 0.859 / -0.040 / 0.089 / 0.657 / -0.025 / 0.089 / 0.780 / -0.063 / 0.089 / 0.478 / -0.040 / 0.089 / 0.653
ig / 0.658 / 0.260 / 0.012* / -0.303 / 0.120 / 0.012* / -0.362 / 0.130 / 0.006* / 0.375 / 0.127 / 0.003* / -0.319 / 0.146 / 0.030*

a and b are the main effect estimates for the numbers of rare alleles of marker A and marker B, respectively; ig represents an estimate of GxG effect in as much as it indicates the

change in the allelic variant association of one marker with the phenotype across the different numbers of rare alleles of the other marker.

Gender refers to female.

* Empirical p-value computed from 500.000 permutations.

Supplementary Material 3_Mascheretti1

Supplementary Material 3.Significant pairwise GxG effects before Bonferroni

correction between the DYX1C1, DCDC2, ROBO1, KIAA0319and GRIN2B markers

on neuropsychological composite.

Memory Digits composite
A: KIAA0319-rs9461045C/T / A: TTRAP-rs2143340A/G
B: GRIN2B-rs2192973C/T
β / St. error / p / β / St. error / p
Intercept / -0.395 / 0.088 / <0.001 / -0.402 / 0.084 / <0.001
a / 0.140 / 0.105 / 0.184 / 0.150 / 0.111 / 0.177
b / 0.040 / 0.113 / 0.727 / 0.038 / 0.106 / 0.718
Gender / -0.051 / 0.092 / 0.583 / -0.036 / 0.089 / 0.686
ig / -0.302 / 0.143 / 0.036* / -0.344 / 0.148 / 0.022*

a and b are the main effect estimates for the numbers of rare alleles of marker A and

marker B, respectively; ig represents an estimate of GxG effect in as much as it indicates

the change in the allelic variant association of one marker with the phenotype across the

different numbers of rare alleles of the other marker.

Gender refers to female.

* Empirical p-value computed from 500.000 permutations.

Supplementary Material 3_Mascheretti1